Bipolar Disorder

SYNLAB and ALCEDIAG recently launched the first blood test to assist in mental health diagnosis in France. The test is aimed at differentiating bipolar disorders from depression. The news may be surprising, given the challenges in diagnosing psychiatric conditions, especially when they share common symptoms such as recurrent depression and bipolar disorder.

Psychiatrists’ reactions to the new test are cautious. Many have echoed the sentiments of the French Association of Biological Psychiatry and Neuropsychopharmacology (AFPBN) and Stéphane Jamain, PhD, director of translational neuropsychiatry research (Inserm U955, Mondor Institute of Biomedical Research), who spoke with this news organization.

Early Diagnosis

Depression and bipolar disorders are two distinct psychiatric illnesses requiring different treatments. Early and accurate diagnosis and appropriate treatment are major challenges for clinicians, especially since untreated or inadequately treated bipolar disorder can lead to significant mental and physical health consequences for patients and their families.

Published studies indicate that it takes an average of 8-10 years, and sometimes even longer, to diagnose bipolar disorder. The diagnosis is based on a psychiatric clinical examination, which is conducted by a specialist using validated questionnaires and evaluation scales.

Early and accurate diagnosis of bipolar disorders that allows for appropriate treatment would be a significant advance for patients and their families. This is what the French laboratories SYNLAB, in partnership with ALCEDIAG, propose through myEDIT-B, a blood test described as “the first validated diagnostic aid test to differentiate depression and bipolar disorders.”

Whether this test, the availability of which has somewhat surprised the psychiatric medical and scientific community, will attract psychiatrists remains to be seen.

The AFPBN stated in a press release that “to date, no test meets conditions for clinical use.” For a diagnostic test to be scientifically valid, ethical, and usable in clinical practice, its development must meet strict criteria, as highlighted by the AFPBN. The approximately 10 criteria include the validation of the scientific results in at least two independent clinical studies or cohorts, satisfactory sensitivity (detection of true positives) and specificity (detection of false negatives), and cost that is ethically responsible and allows patient access, independent of commercial interests.

ALCEDIAG has reported two clinical studies, but only one has been published so far (in Translational Psychiatry) involving 400 patients. In this case, “these patients already had a well-established psychiatric condition, did not quite present the same symptoms between patients with recurrent depression and those with bipolar disorder and were not taking the same treatments,” noted Dr. Jamain.

Differentiating between bipolar disorder and depression is crucial, especially regarding treatments, because antidepressants given to a patient with bipolar disorder can induce a manic shift if they are not accompanied by mood stabilizers, Dr. Jamain acknowledged. Nevertheless, he believes that based on what the laboratory has published, it is difficult to comment on the test at this time.

RNA Editing 

Moreover, myEDIT-B is based on a technique that measures RNA editing modifications of specific markers in patients’ blood, which could lead to differences in amino acids within proteins. The technique is unique to the ALCEDIAG laboratory, which coupled it with an artificial intelligence tool that specifically selected 8 RNA sequences for analysis from thousands of edited sequences to obtain a differential signature for unipolar and bipolar depressions. “This method is niche, the trademark of ALCEDIAG,” said Dr. Jamain, who questions the significance of this “editing” on the periphery of the CNS.

“This technique differs from that adopted by most international consortia, which are very active in this research field. The latter technique compares differences in genome [DNA] nucleotides between individuals in large cohorts involving tens of thousands of people and identifies the most frequently occurring patterns associated with a pathology to deduce a risk of developing a psychiatric illness,” said Jamain. “However, the information provided by these large-scale studies does not allow us to define who is at risk for developing the disease any more than the simple observation of the familial recurrence [heritability] of it does.” 

Scientific Validation 

While ALCEDIAG boasts a sensitivity and specificity of more than 80% for its test, the psychiatric world remains cautious. Interviewed by France Info TV, Marion Leboyer, PhD, general director of the FondaMental Foundation, psychiatrist, and researcher (at AP-HP, Inserm in Créteil, France), highlighted the importance of encouraging research on psychiatric illnesses, especially that which will contribute to the understanding and treatment of patients with bipolar disorders. But she expressed caution regarding the test because of the absence of rigorous scientific validation through clinical trials.

Regarding “ALCEDIAG’s test and its commercial aspect, caution is warranted,” said Dr. Jamain. Only time will tell if psychiatrists will prescribe this €899 test, which currently is not reimbursed by social security (see box below). ALCEDIAG plans to submit a validation dossier to the US Food and Drug Administration.

Test Not Reimbursed by Social Security

The ALCEDIAG test will be available beginning in April 2024, by prescription, in SYNLAB France network laboratories. It is intended for patients aged 18 years and older who are being treated for a moderate or severe depressive episode. Test results are transmitted within 4 weeks to the prescribing psychiatrist, who will confirm the diagnosis to the patient during a consultation. Already available in Italy, this in vitro medical device has a CE-IVD marking. In France, however, it costs €899 and is not reimbursed by social security because of insufficient clinical evidence.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

SYNLAB and ALCEDIAG recently launched the first blood test to assist in mental health diagnosis in France. The test is aimed at differentiating bipolar disorders from depression. The news may be surprising, given the challenges in diagnosing psychiatric conditions, especially when they share common symptoms such as recurrent depression and bipolar disorder.

Psychiatrists’ reactions to the new test are cautious. Many have echoed the sentiments of the French Association of Biological Psychiatry and Neuropsychopharmacology (AFPBN) and Stéphane Jamain, PhD, director of translational neuropsychiatry research (Inserm U955, Mondor Institute of Biomedical Research), who spoke with this news organization.

Early Diagnosis

Depression and bipolar disorders are two distinct psychiatric illnesses requiring different treatments. Early and accurate diagnosis and appropriate treatment are major challenges for clinicians, especially since untreated or inadequately treated bipolar disorder can lead to significant mental and physical health consequences for patients and their families.

Published studies indicate that it takes an average of 8-10 years, and sometimes even longer, to diagnose bipolar disorder. The diagnosis is based on a psychiatric clinical examination, which is conducted by a specialist using validated questionnaires and evaluation scales.

Early and accurate diagnosis of bipolar disorders that allows for appropriate treatment would be a significant advance for patients and their families. This is what the French laboratories SYNLAB, in partnership with ALCEDIAG, propose through myEDIT-B, a blood test described as “the first validated diagnostic aid test to differentiate depression and bipolar disorders.”

Whether this test, the availability of which has somewhat surprised the psychiatric medical and scientific community, will attract psychiatrists remains to be seen.

The AFPBN stated in a press release that “to date, no test meets conditions for clinical use.” For a diagnostic test to be scientifically valid, ethical, and usable in clinical practice, its development must meet strict criteria, as highlighted by the AFPBN. The approximately 10 criteria include the validation of the scientific results in at least two independent clinical studies or cohorts, satisfactory sensitivity (detection of true positives) and specificity (detection of false negatives), and cost that is ethically responsible and allows patient access, independent of commercial interests.

ALCEDIAG has reported two clinical studies, but only one has been published so far (in Translational Psychiatry) involving 400 patients. In this case, “these patients already had a well-established psychiatric condition, did not quite present the same symptoms between patients with recurrent depression and those with bipolar disorder and were not taking the same treatments,” noted Dr. Jamain.

Differentiating between bipolar disorder and depression is crucial, especially regarding treatments, because antidepressants given to a patient with bipolar disorder can induce a manic shift if they are not accompanied by mood stabilizers, Dr. Jamain acknowledged. Nevertheless, he believes that based on what the laboratory has published, it is difficult to comment on the test at this time.

RNA Editing 

Moreover, myEDIT-B is based on a technique that measures RNA editing modifications of specific markers in patients’ blood, which could lead to differences in amino acids within proteins. The technique is unique to the ALCEDIAG laboratory, which coupled it with an artificial intelligence tool that specifically selected 8 RNA sequences for analysis from thousands of edited sequences to obtain a differential signature for unipolar and bipolar depressions. “This method is niche, the trademark of ALCEDIAG,” said Dr. Jamain, who questions the significance of this “editing” on the periphery of the CNS.

“This technique differs from that adopted by most international consortia, which are very active in this research field. The latter technique compares differences in genome [DNA] nucleotides between individuals in large cohorts involving tens of thousands of people and identifies the most frequently occurring patterns associated with a pathology to deduce a risk of developing a psychiatric illness,” said Jamain. “However, the information provided by these large-scale studies does not allow us to define who is at risk for developing the disease any more than the simple observation of the familial recurrence [heritability] of it does.” 

Scientific Validation 

While ALCEDIAG boasts a sensitivity and specificity of more than 80% for its test, the psychiatric world remains cautious. Interviewed by France Info TV, Marion Leboyer, PhD, general director of the FondaMental Foundation, psychiatrist, and researcher (at AP-HP, Inserm in Créteil, France), highlighted the importance of encouraging research on psychiatric illnesses, especially that which will contribute to the understanding and treatment of patients with bipolar disorders. But she expressed caution regarding the test because of the absence of rigorous scientific validation through clinical trials.

Regarding “ALCEDIAG’s test and its commercial aspect, caution is warranted,” said Dr. Jamain. Only time will tell if psychiatrists will prescribe this €899 test, which currently is not reimbursed by social security (see box below). ALCEDIAG plans to submit a validation dossier to the US Food and Drug Administration.

Test Not Reimbursed by Social Security

The ALCEDIAG test will be available beginning in April 2024, by prescription, in SYNLAB France network laboratories. It is intended for patients aged 18 years and older who are being treated for a moderate or severe depressive episode. Test results are transmitted within 4 weeks to the prescribing psychiatrist, who will confirm the diagnosis to the patient during a consultation. Already available in Italy, this in vitro medical device has a CE-IVD marking. In France, however, it costs €899 and is not reimbursed by social security because of insufficient clinical evidence.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

SYNLAB and ALCEDIAG recently launched the first blood test to assist in mental health diagnosis in France. The test is aimed at differentiating bipolar disorders from depression. The news may be surprising, given the challenges in diagnosing psychiatric conditions, especially when they share common symptoms such as recurrent depression and bipolar disorder.

Psychiatrists’ reactions to the new test are cautious. Many have echoed the sentiments of the French Association of Biological Psychiatry and Neuropsychopharmacology (AFPBN) and Stéphane Jamain, PhD, director of translational neuropsychiatry research (Inserm U955, Mondor Institute of Biomedical Research), who spoke with this news organization.

Early Diagnosis

Depression and bipolar disorders are two distinct psychiatric illnesses requiring different treatments. Early and accurate diagnosis and appropriate treatment are major challenges for clinicians, especially since untreated or inadequately treated bipolar disorder can lead to significant mental and physical health consequences for patients and their families.

Published studies indicate that it takes an average of 8-10 years, and sometimes even longer, to diagnose bipolar disorder. The diagnosis is based on a psychiatric clinical examination, which is conducted by a specialist using validated questionnaires and evaluation scales.

Early and accurate diagnosis of bipolar disorders that allows for appropriate treatment would be a significant advance for patients and their families. This is what the French laboratories SYNLAB, in partnership with ALCEDIAG, propose through myEDIT-B, a blood test described as “the first validated diagnostic aid test to differentiate depression and bipolar disorders.”

Whether this test, the availability of which has somewhat surprised the psychiatric medical and scientific community, will attract psychiatrists remains to be seen.

The AFPBN stated in a press release that “to date, no test meets conditions for clinical use.” For a diagnostic test to be scientifically valid, ethical, and usable in clinical practice, its development must meet strict criteria, as highlighted by the AFPBN. The approximately 10 criteria include the validation of the scientific results in at least two independent clinical studies or cohorts, satisfactory sensitivity (detection of true positives) and specificity (detection of false negatives), and cost that is ethically responsible and allows patient access, independent of commercial interests.

ALCEDIAG has reported two clinical studies, but only one has been published so far (in Translational Psychiatry) involving 400 patients. In this case, “these patients already had a well-established psychiatric condition, did not quite present the same symptoms between patients with recurrent depression and those with bipolar disorder and were not taking the same treatments,” noted Dr. Jamain.

Differentiating between bipolar disorder and depression is crucial, especially regarding treatments, because antidepressants given to a patient with bipolar disorder can induce a manic shift if they are not accompanied by mood stabilizers, Dr. Jamain acknowledged. Nevertheless, he believes that based on what the laboratory has published, it is difficult to comment on the test at this time.

RNA Editing 

Moreover, myEDIT-B is based on a technique that measures RNA editing modifications of specific markers in patients’ blood, which could lead to differences in amino acids within proteins. The technique is unique to the ALCEDIAG laboratory, which coupled it with an artificial intelligence tool that specifically selected 8 RNA sequences for analysis from thousands of edited sequences to obtain a differential signature for unipolar and bipolar depressions. “This method is niche, the trademark of ALCEDIAG,” said Dr. Jamain, who questions the significance of this “editing” on the periphery of the CNS.

“This technique differs from that adopted by most international consortia, which are very active in this research field. The latter technique compares differences in genome [DNA] nucleotides between individuals in large cohorts involving tens of thousands of people and identifies the most frequently occurring patterns associated with a pathology to deduce a risk of developing a psychiatric illness,” said Jamain. “However, the information provided by these large-scale studies does not allow us to define who is at risk for developing the disease any more than the simple observation of the familial recurrence [heritability] of it does.” 

Scientific Validation 

While ALCEDIAG boasts a sensitivity and specificity of more than 80% for its test, the psychiatric world remains cautious. Interviewed by France Info TV, Marion Leboyer, PhD, general director of the FondaMental Foundation, psychiatrist, and researcher (at AP-HP, Inserm in Créteil, France), highlighted the importance of encouraging research on psychiatric illnesses, especially that which will contribute to the understanding and treatment of patients with bipolar disorders. But she expressed caution regarding the test because of the absence of rigorous scientific validation through clinical trials.

Regarding “ALCEDIAG’s test and its commercial aspect, caution is warranted,” said Dr. Jamain. Only time will tell if psychiatrists will prescribe this €899 test, which currently is not reimbursed by social security (see box below). ALCEDIAG plans to submit a validation dossier to the US Food and Drug Administration.

Test Not Reimbursed by Social Security

The ALCEDIAG test will be available beginning in April 2024, by prescription, in SYNLAB France network laboratories. It is intended for patients aged 18 years and older who are being treated for a moderate or severe depressive episode. Test results are transmitted within 4 weeks to the prescribing psychiatrist, who will confirm the diagnosis to the patient during a consultation. Already available in Italy, this in vitro medical device has a CE-IVD marking. In France, however, it costs €899 and is not reimbursed by social security because of insufficient clinical evidence.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Bipolar 1 disorder is a chronic and disabling mental health disorder that results in cognitive, functional, and social impairments associated with an increased risk for hospitalization and premature death.

Bipolar 1 disorder is characterized by manic episodes that last for at least 7 days, or manic symptoms that are so severe that they require immediate medical care. Depressive episodes also occur.

Dr Michael Thase, from the University of Pennsylvania, explains that although ongoing treatment is essential to prevent relapse and recurrence, particularly after a hospitalization, adherence can be serious problem.

Long-acting injectable (LAI) agents can act as a bridge between oral medications initiated in hospital and ongoing prevention therapies.

Dr Thase says LAIs can help improve adherence and patient quality of life, and are effective against relapses in adults with bipolar 1 disorder.

--

Michael E. Thase, MD, Professor of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Michael E. Thase, MD, has disclosed the following relevant financial relationships:

Serve(d) as an advisor or consultant for: Acadia, Inc; Akili, Inc; Alkermes PLC; Allergan, Inc; Axsome Therapeutics, Inc; Biohaven, Inc; Bocemtium Consulting, SL; Boehringer Ingelheim International; CatalYm GmbH; Clexio Biosciences; Gerson Lehrman Group, Inc; H Lundbeck, A/S; Jazz Pharmaceuticals; Janssen; Johnson & Johnson; Luye Pharma Group, Ltd; Merck & Company, Inc; Otsuka Pharmaceuticals Company, Ltd; Pfizer, Inc; Sage Pharmaceuticals; Seelos Therapeutics; Sunovion Pharmaceuticals, Inc; Takeda Pharmaceutical Company, Ltd

Receive research funding from: Acadia, Inc; Allergan, Inc; AssureRx; Axsome Therapeutics, Inc; Biohaven, Inc; Intracellular, Inc; Johnson & Johnson; Otsuka Pharmaceuticals Company, Ltd; Patient-Centered Outcomes Research Institute (PCORI); Takeda Pharmaceutical Company, Ltd

Receive royalties from: American Psychiatric Foundation; Guilford Publications; Herald House; Kluwer-Wolters; W.W. Norton & Company, Inc

Bipolar 1 disorder is a chronic and disabling mental health disorder that results in cognitive, functional, and social impairments associated with an increased risk for hospitalization and premature death.

Bipolar 1 disorder is characterized by manic episodes that last for at least 7 days, or manic symptoms that are so severe that they require immediate medical care. Depressive episodes also occur.

Dr Michael Thase, from the University of Pennsylvania, explains that although ongoing treatment is essential to prevent relapse and recurrence, particularly after a hospitalization, adherence can be serious problem.

Long-acting injectable (LAI) agents can act as a bridge between oral medications initiated in hospital and ongoing prevention therapies.

Dr Thase says LAIs can help improve adherence and patient quality of life, and are effective against relapses in adults with bipolar 1 disorder.

--

Michael E. Thase, MD, Professor of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Michael E. Thase, MD, has disclosed the following relevant financial relationships:

Serve(d) as an advisor or consultant for: Acadia, Inc; Akili, Inc; Alkermes PLC; Allergan, Inc; Axsome Therapeutics, Inc; Biohaven, Inc; Bocemtium Consulting, SL; Boehringer Ingelheim International; CatalYm GmbH; Clexio Biosciences; Gerson Lehrman Group, Inc; H Lundbeck, A/S; Jazz Pharmaceuticals; Janssen; Johnson & Johnson; Luye Pharma Group, Ltd; Merck & Company, Inc; Otsuka Pharmaceuticals Company, Ltd; Pfizer, Inc; Sage Pharmaceuticals; Seelos Therapeutics; Sunovion Pharmaceuticals, Inc; Takeda Pharmaceutical Company, Ltd

Receive research funding from: Acadia, Inc; Allergan, Inc; AssureRx; Axsome Therapeutics, Inc; Biohaven, Inc; Intracellular, Inc; Johnson & Johnson; Otsuka Pharmaceuticals Company, Ltd; Patient-Centered Outcomes Research Institute (PCORI); Takeda Pharmaceutical Company, Ltd

Receive royalties from: American Psychiatric Foundation; Guilford Publications; Herald House; Kluwer-Wolters; W.W. Norton & Company, Inc

Bipolar 1 disorder is a chronic and disabling mental health disorder that results in cognitive, functional, and social impairments associated with an increased risk for hospitalization and premature death.

Bipolar 1 disorder is characterized by manic episodes that last for at least 7 days, or manic symptoms that are so severe that they require immediate medical care. Depressive episodes also occur.

Dr Michael Thase, from the University of Pennsylvania, explains that although ongoing treatment is essential to prevent relapse and recurrence, particularly after a hospitalization, adherence can be serious problem.

Long-acting injectable (LAI) agents can act as a bridge between oral medications initiated in hospital and ongoing prevention therapies.

Dr Thase says LAIs can help improve adherence and patient quality of life, and are effective against relapses in adults with bipolar 1 disorder.

--

Michael E. Thase, MD, Professor of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

Michael E. Thase, MD, has disclosed the following relevant financial relationships:

Serve(d) as an advisor or consultant for: Acadia, Inc; Akili, Inc; Alkermes PLC; Allergan, Inc; Axsome Therapeutics, Inc; Biohaven, Inc; Bocemtium Consulting, SL; Boehringer Ingelheim International; CatalYm GmbH; Clexio Biosciences; Gerson Lehrman Group, Inc; H Lundbeck, A/S; Jazz Pharmaceuticals; Janssen; Johnson & Johnson; Luye Pharma Group, Ltd; Merck & Company, Inc; Otsuka Pharmaceuticals Company, Ltd; Pfizer, Inc; Sage Pharmaceuticals; Seelos Therapeutics; Sunovion Pharmaceuticals, Inc; Takeda Pharmaceutical Company, Ltd

Receive research funding from: Acadia, Inc; Allergan, Inc; AssureRx; Axsome Therapeutics, Inc; Biohaven, Inc; Intracellular, Inc; Johnson & Johnson; Otsuka Pharmaceuticals Company, Ltd; Patient-Centered Outcomes Research Institute (PCORI); Takeda Pharmaceutical Company, Ltd

Receive royalties from: American Psychiatric Foundation; Guilford Publications; Herald House; Kluwer-Wolters; W.W. Norton & Company, Inc

Recent research highlights the potential role of an atypical antipsychotic to treat anxiety, a prevalent and undertreated symptom in bipolar I disorder (BPD). Notably, investigators said, the drug comes without the typical metabolic side effects, including weight gain, associated with this drug class.

A post hoc analysis of pooled data from two trials comparing two different doses of cariprazine (Vraylar) to placebo showed it was consistently effective not only in alleviating bipolar depression but also in improving symptoms of anxiety.

“Since this was a post hoc analysis, one has to be careful about not overstating the findings,” said study investigator Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Toronto, Ontario, Canada, and head of the Mood Disorders Psychopharmacology Unit.

“But what we can say is that anxiety has been an under-researched, undertreated symptom dimension in BPD, and these findings about cariprazine are very promising,” said Dr. McIntyre, chair and executive director of the Brain and Cognition Discovery Foundation, also in Toronto.

The analysis was published in International Clinical Psychopharmacology) and was presented as a poster at the 2023 Neuroscience Education Institute, Colorado Springs, Colorado.
 

Ubiquitous, Common, Hazardous

Anxiety in BPD is “ubiquitous, common, and hazardous,” Dr. McIntyre said. “We talk so much about depression and mania as cardinal presentations, but someone could make a case that in that trifecta, we’re missing anxiety.”

In patients with BPD and anxiety, “the index episode is much more difficult to treat, there’s a longer time to remission, lower rates of recovery, and a shorter time to recurrence,” noted Dr. McIntyre, chair of the board of the Depression and Bipolar Support Alliance.

Anxiety also may “represent a portent of other things that can add more to the trouble, like alcohol, illicit drugs, or cannabis use — especially now that cannabis is no longer illegal,” Dr. McIntyre said.

Unfortunately, he said, “there hasn’t been an organized, systematic approach to developing a therapy for anxiety in BPD.” Rather, patients are prescribed benzodiazepines, gabapentinoids, or selective serotonin reuptake inhibitors, all of which have limitations, he added.

Some atypical antipsychotics such as quetiapine have been shown to be helpful with anxiety but “have a lot of baggage and side effects — especially sedation, somnolence, weight gain, and metabolic problems,” Dr. McIntyre noted.

Cariprazine is a dopamine D3-preferring D3/D2 partial agonist, a serotonin 5-HT1A receptor partial agonist, and 5-HT2B receptor antagonist, which has shown anxiolytic-like activity in rodent models.

It was approved by the US Food and Drug Administration to treat mania, depression, and mixed episodes of BPD in 2015 and BPD in 2019.

Dr. McIntyre and his team believed there was an opportunity in the completed randomized controlled trials of cariprazine in BPD to conduct a post hoc analysis of its impact on anxiety.
 

‘Cornerstone Mood Stabilizer’

The researchers pooled data from two phase 3, randomized, double-blind, placebo-controlled studies in adults with BPD experiencing a current major depressive episode.

The pooled intention-to-treat population consisted of 952 patients with BPD (mean age, ~43 years; 62% female) randomized to receive either 1.5 mg/d, 3 mg/d of cariprazine, or placebo. Patients were divided into two subsets: Lower or higher anxiety (defined as a Hamilton Anxiety Rating Scale [HAM-A] total score of < 18 and ≥ 18, respectively). Patients also completed the Montgomery-Åsberg Rating Scale (MADRS).

A third of the patients received a placebo, a third received the 1.5 mg/d dose, and a third received the 3 mg/d dose. Demographic and baseline characteristics were similar between the subsets.

Results showed there was a statistically significant change in HAM-A total score for cariprazine 1.5 mg/d (P = .0027). The investigators also found a statistically significant change in MADRS total score change for cariprazine 1.5 mg (P = .0200) in the higher anxiety subset. The rate of remission was significantly greater for cariprazine 1.5 mg/d in the higher and lower anxiety subsets (P = .0172 and P = .0004, respectively).

In addition, the change in HAM-A total score change was statistically significant for cariprazine 1.5 mg/d in the higher anxiety subgroup (P = .0105) and the 3 mg/d dose in the lower anxiety subgroup (P = .0441).

Dr. McIntyre hopes these findings can be replicated in other trials.

“Clinically, I find that many patients who take cariprazine don’t require as many benzodiazepines or other medications for anxiety, and it’s one of the better-tolerated medications without metabolic complications or weight gain, so it’s become a cornerstone mood stabilizer,” he said.
 

Polypharmacy Avoided

Another recent study retrospectively analyzed medical records of close to 40 adult patients with BPD I who were receiving treatment with aripiprazole for bipolar depression and then switched to cariprazine.

“We wanted to conduct a study in depressed patients who had gained weight on aripiprazole and then directly switched to cariprazine. It improved their mood and helped mitigate weight gain, thereby avoiding polypharmacy of additional antidepressants and weight loss agents,” said study investigator Maxwell Zachary Price, a medical student at Hackensack Meridian School of Medicine, Nutley, New Jersey.

“In our general outpatient psychiatry practice, we’ve treated many adult patients with oral aripiprazole for maintenance of BPD,” the study’s senior investigator, Richard Price, MD, clinical assistant professor of psychiatry at Weill Cornell Medical College, New York City, added.

Aripiprazole is associated with weight gain. Moreover, aripiprazole “hasn’t shown efficacy in managing BPD,” he said.

Most patients in Dr. Price’s practice are insured through Medicaid, which mandates treatment with aripiprazole before covering cariprazine. “We noticed their weight had been creeping up over the years, and they also were experiencing depressive symptoms,” he said.

The requirement to initiate treatment with aripiprazole before switching to cariprazine offered Dr. Price an opportunity to compare the two agents in this real-world setting by retrospectively reviewing the charts of 37 patients with BPD (23 females and 14 males who made the switch). The patients had been taking aripiprazole for a mean duration of 94.9 weeks and had experienced a mean increase in body weight of 16.1% ± 12.3% on aripiprazole before switching.

Patients who were taking 2 mg-10 mg of aripiprazole were switched to 1.5 mg of cariprazine, while those taking ≥ 15 mg of aripiprazole were switched to 3 mg of cariprazine.

“Patients tolerated the switch well and maintained stability during the transition,” and “no patients discontinued cariprazine during the study,” Dr. Price said.

After a mean duration of 36.7 weeks (range, 1-127 weeks), the patients showed a decrease in Clinical Global Impression-Bipolar Severity of Illness Scale score from a mean of 5.0 ± 0.9 to a mean of 2.8 ± 0.7 (t = −12.75, P < .00001).

The patients’ weight dropped from a mean of 90.3± 21.5 kg on aripiprazole to a mean of 83.9 ± 19.2 kg on cariprazine (t = −4.22, P < .001).

Two patients experienced initial nausea that resolved by taking the medication with food, and two experienced initial restlessness that resolved with dosage reduction.

“We found that the patients were lighter in mood, body habitus and weight, and less agitated and their mental alertness and concentration improved as well,” said Dr. Price. He hopes that further research in randomized blinded trials will corroborate the findings.
 

Hypothesis-Generating Research

Joseph Cerimele, MD, MPH, associate professor of psychiatry and behavioral sciences, University of Washington, Division of Population Health, UW Medicine, Seattle, Washington, said the research findings are “hypothesis-generating.”

Dr. Ciremele, who wasn’t involved with either study, said many clinicians and researchers are trying to tailor treatment options to match patient characteristics, and these studies and other similar research, “help us all ask questions related to concurrent symptoms in bipolar depression.”

However, the post hoc analysis was a secondary analysis of an efficacy trial where individuals with concurrent anxiety disorders were excluded. “So, a next step might be to evaluate this and other treatments in individuals with BPD and concurrent anxiety disorders,” he said.

The study by Jain et al was funded by AbbVie. Dr. McIntyre had received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics Inc., Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome Therapeutics, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular Therapies, NewBridge Pharmaceuticals, Viatris, Abbvie, and Atai Life Sciences. Dr. McIntyre is the CEO of Braxia Scientific Corp. His coauthors’ disclosures are listed in the original paper. Dr. Price had received honoraria from AbbVie, Alkermes, Allergan, Intra-Cellular Therapies, Janssen, Jazz, Lundbeck, Neuronetics, Otsuka, and Supernus. Mr. Price and Dr. Cerimele reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Recent research highlights the potential role of an atypical antipsychotic to treat anxiety, a prevalent and undertreated symptom in bipolar I disorder (BPD). Notably, investigators said, the drug comes without the typical metabolic side effects, including weight gain, associated with this drug class.

A post hoc analysis of pooled data from two trials comparing two different doses of cariprazine (Vraylar) to placebo showed it was consistently effective not only in alleviating bipolar depression but also in improving symptoms of anxiety.

“Since this was a post hoc analysis, one has to be careful about not overstating the findings,” said study investigator Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Toronto, Ontario, Canada, and head of the Mood Disorders Psychopharmacology Unit.

“But what we can say is that anxiety has been an under-researched, undertreated symptom dimension in BPD, and these findings about cariprazine are very promising,” said Dr. McIntyre, chair and executive director of the Brain and Cognition Discovery Foundation, also in Toronto.

The analysis was published in International Clinical Psychopharmacology) and was presented as a poster at the 2023 Neuroscience Education Institute, Colorado Springs, Colorado.
 

Ubiquitous, Common, Hazardous

Anxiety in BPD is “ubiquitous, common, and hazardous,” Dr. McIntyre said. “We talk so much about depression and mania as cardinal presentations, but someone could make a case that in that trifecta, we’re missing anxiety.”

In patients with BPD and anxiety, “the index episode is much more difficult to treat, there’s a longer time to remission, lower rates of recovery, and a shorter time to recurrence,” noted Dr. McIntyre, chair of the board of the Depression and Bipolar Support Alliance.

Anxiety also may “represent a portent of other things that can add more to the trouble, like alcohol, illicit drugs, or cannabis use — especially now that cannabis is no longer illegal,” Dr. McIntyre said.

Unfortunately, he said, “there hasn’t been an organized, systematic approach to developing a therapy for anxiety in BPD.” Rather, patients are prescribed benzodiazepines, gabapentinoids, or selective serotonin reuptake inhibitors, all of which have limitations, he added.

Some atypical antipsychotics such as quetiapine have been shown to be helpful with anxiety but “have a lot of baggage and side effects — especially sedation, somnolence, weight gain, and metabolic problems,” Dr. McIntyre noted.

Cariprazine is a dopamine D3-preferring D3/D2 partial agonist, a serotonin 5-HT1A receptor partial agonist, and 5-HT2B receptor antagonist, which has shown anxiolytic-like activity in rodent models.

It was approved by the US Food and Drug Administration to treat mania, depression, and mixed episodes of BPD in 2015 and BPD in 2019.

Dr. McIntyre and his team believed there was an opportunity in the completed randomized controlled trials of cariprazine in BPD to conduct a post hoc analysis of its impact on anxiety.
 

‘Cornerstone Mood Stabilizer’

The researchers pooled data from two phase 3, randomized, double-blind, placebo-controlled studies in adults with BPD experiencing a current major depressive episode.

The pooled intention-to-treat population consisted of 952 patients with BPD (mean age, ~43 years; 62% female) randomized to receive either 1.5 mg/d, 3 mg/d of cariprazine, or placebo. Patients were divided into two subsets: Lower or higher anxiety (defined as a Hamilton Anxiety Rating Scale [HAM-A] total score of < 18 and ≥ 18, respectively). Patients also completed the Montgomery-Åsberg Rating Scale (MADRS).

A third of the patients received a placebo, a third received the 1.5 mg/d dose, and a third received the 3 mg/d dose. Demographic and baseline characteristics were similar between the subsets.

Results showed there was a statistically significant change in HAM-A total score for cariprazine 1.5 mg/d (P = .0027). The investigators also found a statistically significant change in MADRS total score change for cariprazine 1.5 mg (P = .0200) in the higher anxiety subset. The rate of remission was significantly greater for cariprazine 1.5 mg/d in the higher and lower anxiety subsets (P = .0172 and P = .0004, respectively).

In addition, the change in HAM-A total score change was statistically significant for cariprazine 1.5 mg/d in the higher anxiety subgroup (P = .0105) and the 3 mg/d dose in the lower anxiety subgroup (P = .0441).

Dr. McIntyre hopes these findings can be replicated in other trials.

“Clinically, I find that many patients who take cariprazine don’t require as many benzodiazepines or other medications for anxiety, and it’s one of the better-tolerated medications without metabolic complications or weight gain, so it’s become a cornerstone mood stabilizer,” he said.
 

Polypharmacy Avoided

Another recent study retrospectively analyzed medical records of close to 40 adult patients with BPD I who were receiving treatment with aripiprazole for bipolar depression and then switched to cariprazine.

“We wanted to conduct a study in depressed patients who had gained weight on aripiprazole and then directly switched to cariprazine. It improved their mood and helped mitigate weight gain, thereby avoiding polypharmacy of additional antidepressants and weight loss agents,” said study investigator Maxwell Zachary Price, a medical student at Hackensack Meridian School of Medicine, Nutley, New Jersey.

“In our general outpatient psychiatry practice, we’ve treated many adult patients with oral aripiprazole for maintenance of BPD,” the study’s senior investigator, Richard Price, MD, clinical assistant professor of psychiatry at Weill Cornell Medical College, New York City, added.

Aripiprazole is associated with weight gain. Moreover, aripiprazole “hasn’t shown efficacy in managing BPD,” he said.

Most patients in Dr. Price’s practice are insured through Medicaid, which mandates treatment with aripiprazole before covering cariprazine. “We noticed their weight had been creeping up over the years, and they also were experiencing depressive symptoms,” he said.

The requirement to initiate treatment with aripiprazole before switching to cariprazine offered Dr. Price an opportunity to compare the two agents in this real-world setting by retrospectively reviewing the charts of 37 patients with BPD (23 females and 14 males who made the switch). The patients had been taking aripiprazole for a mean duration of 94.9 weeks and had experienced a mean increase in body weight of 16.1% ± 12.3% on aripiprazole before switching.

Patients who were taking 2 mg-10 mg of aripiprazole were switched to 1.5 mg of cariprazine, while those taking ≥ 15 mg of aripiprazole were switched to 3 mg of cariprazine.

“Patients tolerated the switch well and maintained stability during the transition,” and “no patients discontinued cariprazine during the study,” Dr. Price said.

After a mean duration of 36.7 weeks (range, 1-127 weeks), the patients showed a decrease in Clinical Global Impression-Bipolar Severity of Illness Scale score from a mean of 5.0 ± 0.9 to a mean of 2.8 ± 0.7 (t = −12.75, P < .00001).

The patients’ weight dropped from a mean of 90.3± 21.5 kg on aripiprazole to a mean of 83.9 ± 19.2 kg on cariprazine (t = −4.22, P < .001).

Two patients experienced initial nausea that resolved by taking the medication with food, and two experienced initial restlessness that resolved with dosage reduction.

“We found that the patients were lighter in mood, body habitus and weight, and less agitated and their mental alertness and concentration improved as well,” said Dr. Price. He hopes that further research in randomized blinded trials will corroborate the findings.
 

Hypothesis-Generating Research

Joseph Cerimele, MD, MPH, associate professor of psychiatry and behavioral sciences, University of Washington, Division of Population Health, UW Medicine, Seattle, Washington, said the research findings are “hypothesis-generating.”

Dr. Ciremele, who wasn’t involved with either study, said many clinicians and researchers are trying to tailor treatment options to match patient characteristics, and these studies and other similar research, “help us all ask questions related to concurrent symptoms in bipolar depression.”

However, the post hoc analysis was a secondary analysis of an efficacy trial where individuals with concurrent anxiety disorders were excluded. “So, a next step might be to evaluate this and other treatments in individuals with BPD and concurrent anxiety disorders,” he said.

The study by Jain et al was funded by AbbVie. Dr. McIntyre had received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics Inc., Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome Therapeutics, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular Therapies, NewBridge Pharmaceuticals, Viatris, Abbvie, and Atai Life Sciences. Dr. McIntyre is the CEO of Braxia Scientific Corp. His coauthors’ disclosures are listed in the original paper. Dr. Price had received honoraria from AbbVie, Alkermes, Allergan, Intra-Cellular Therapies, Janssen, Jazz, Lundbeck, Neuronetics, Otsuka, and Supernus. Mr. Price and Dr. Cerimele reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Recent research highlights the potential role of an atypical antipsychotic to treat anxiety, a prevalent and undertreated symptom in bipolar I disorder (BPD). Notably, investigators said, the drug comes without the typical metabolic side effects, including weight gain, associated with this drug class.

A post hoc analysis of pooled data from two trials comparing two different doses of cariprazine (Vraylar) to placebo showed it was consistently effective not only in alleviating bipolar depression but also in improving symptoms of anxiety.

“Since this was a post hoc analysis, one has to be careful about not overstating the findings,” said study investigator Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Toronto, Ontario, Canada, and head of the Mood Disorders Psychopharmacology Unit.

“But what we can say is that anxiety has been an under-researched, undertreated symptom dimension in BPD, and these findings about cariprazine are very promising,” said Dr. McIntyre, chair and executive director of the Brain and Cognition Discovery Foundation, also in Toronto.

The analysis was published in International Clinical Psychopharmacology) and was presented as a poster at the 2023 Neuroscience Education Institute, Colorado Springs, Colorado.
 

Ubiquitous, Common, Hazardous

Anxiety in BPD is “ubiquitous, common, and hazardous,” Dr. McIntyre said. “We talk so much about depression and mania as cardinal presentations, but someone could make a case that in that trifecta, we’re missing anxiety.”

In patients with BPD and anxiety, “the index episode is much more difficult to treat, there’s a longer time to remission, lower rates of recovery, and a shorter time to recurrence,” noted Dr. McIntyre, chair of the board of the Depression and Bipolar Support Alliance.

Anxiety also may “represent a portent of other things that can add more to the trouble, like alcohol, illicit drugs, or cannabis use — especially now that cannabis is no longer illegal,” Dr. McIntyre said.

Unfortunately, he said, “there hasn’t been an organized, systematic approach to developing a therapy for anxiety in BPD.” Rather, patients are prescribed benzodiazepines, gabapentinoids, or selective serotonin reuptake inhibitors, all of which have limitations, he added.

Some atypical antipsychotics such as quetiapine have been shown to be helpful with anxiety but “have a lot of baggage and side effects — especially sedation, somnolence, weight gain, and metabolic problems,” Dr. McIntyre noted.

Cariprazine is a dopamine D3-preferring D3/D2 partial agonist, a serotonin 5-HT1A receptor partial agonist, and 5-HT2B receptor antagonist, which has shown anxiolytic-like activity in rodent models.

It was approved by the US Food and Drug Administration to treat mania, depression, and mixed episodes of BPD in 2015 and BPD in 2019.

Dr. McIntyre and his team believed there was an opportunity in the completed randomized controlled trials of cariprazine in BPD to conduct a post hoc analysis of its impact on anxiety.
 

‘Cornerstone Mood Stabilizer’

The researchers pooled data from two phase 3, randomized, double-blind, placebo-controlled studies in adults with BPD experiencing a current major depressive episode.

The pooled intention-to-treat population consisted of 952 patients with BPD (mean age, ~43 years; 62% female) randomized to receive either 1.5 mg/d, 3 mg/d of cariprazine, or placebo. Patients were divided into two subsets: Lower or higher anxiety (defined as a Hamilton Anxiety Rating Scale [HAM-A] total score of < 18 and ≥ 18, respectively). Patients also completed the Montgomery-Åsberg Rating Scale (MADRS).

A third of the patients received a placebo, a third received the 1.5 mg/d dose, and a third received the 3 mg/d dose. Demographic and baseline characteristics were similar between the subsets.

Results showed there was a statistically significant change in HAM-A total score for cariprazine 1.5 mg/d (P = .0027). The investigators also found a statistically significant change in MADRS total score change for cariprazine 1.5 mg (P = .0200) in the higher anxiety subset. The rate of remission was significantly greater for cariprazine 1.5 mg/d in the higher and lower anxiety subsets (P = .0172 and P = .0004, respectively).

In addition, the change in HAM-A total score change was statistically significant for cariprazine 1.5 mg/d in the higher anxiety subgroup (P = .0105) and the 3 mg/d dose in the lower anxiety subgroup (P = .0441).

Dr. McIntyre hopes these findings can be replicated in other trials.

“Clinically, I find that many patients who take cariprazine don’t require as many benzodiazepines or other medications for anxiety, and it’s one of the better-tolerated medications without metabolic complications or weight gain, so it’s become a cornerstone mood stabilizer,” he said.
 

Polypharmacy Avoided

Another recent study retrospectively analyzed medical records of close to 40 adult patients with BPD I who were receiving treatment with aripiprazole for bipolar depression and then switched to cariprazine.

“We wanted to conduct a study in depressed patients who had gained weight on aripiprazole and then directly switched to cariprazine. It improved their mood and helped mitigate weight gain, thereby avoiding polypharmacy of additional antidepressants and weight loss agents,” said study investigator Maxwell Zachary Price, a medical student at Hackensack Meridian School of Medicine, Nutley, New Jersey.

“In our general outpatient psychiatry practice, we’ve treated many adult patients with oral aripiprazole for maintenance of BPD,” the study’s senior investigator, Richard Price, MD, clinical assistant professor of psychiatry at Weill Cornell Medical College, New York City, added.

Aripiprazole is associated with weight gain. Moreover, aripiprazole “hasn’t shown efficacy in managing BPD,” he said.

Most patients in Dr. Price’s practice are insured through Medicaid, which mandates treatment with aripiprazole before covering cariprazine. “We noticed their weight had been creeping up over the years, and they also were experiencing depressive symptoms,” he said.

The requirement to initiate treatment with aripiprazole before switching to cariprazine offered Dr. Price an opportunity to compare the two agents in this real-world setting by retrospectively reviewing the charts of 37 patients with BPD (23 females and 14 males who made the switch). The patients had been taking aripiprazole for a mean duration of 94.9 weeks and had experienced a mean increase in body weight of 16.1% ± 12.3% on aripiprazole before switching.

Patients who were taking 2 mg-10 mg of aripiprazole were switched to 1.5 mg of cariprazine, while those taking ≥ 15 mg of aripiprazole were switched to 3 mg of cariprazine.

“Patients tolerated the switch well and maintained stability during the transition,” and “no patients discontinued cariprazine during the study,” Dr. Price said.

After a mean duration of 36.7 weeks (range, 1-127 weeks), the patients showed a decrease in Clinical Global Impression-Bipolar Severity of Illness Scale score from a mean of 5.0 ± 0.9 to a mean of 2.8 ± 0.7 (t = −12.75, P < .00001).

The patients’ weight dropped from a mean of 90.3± 21.5 kg on aripiprazole to a mean of 83.9 ± 19.2 kg on cariprazine (t = −4.22, P < .001).

Two patients experienced initial nausea that resolved by taking the medication with food, and two experienced initial restlessness that resolved with dosage reduction.

“We found that the patients were lighter in mood, body habitus and weight, and less agitated and their mental alertness and concentration improved as well,” said Dr. Price. He hopes that further research in randomized blinded trials will corroborate the findings.
 

Hypothesis-Generating Research

Joseph Cerimele, MD, MPH, associate professor of psychiatry and behavioral sciences, University of Washington, Division of Population Health, UW Medicine, Seattle, Washington, said the research findings are “hypothesis-generating.”

Dr. Ciremele, who wasn’t involved with either study, said many clinicians and researchers are trying to tailor treatment options to match patient characteristics, and these studies and other similar research, “help us all ask questions related to concurrent symptoms in bipolar depression.”

However, the post hoc analysis was a secondary analysis of an efficacy trial where individuals with concurrent anxiety disorders were excluded. “So, a next step might be to evaluate this and other treatments in individuals with BPD and concurrent anxiety disorders,” he said.

The study by Jain et al was funded by AbbVie. Dr. McIntyre had received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics Inc., Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome Therapeutics, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular Therapies, NewBridge Pharmaceuticals, Viatris, Abbvie, and Atai Life Sciences. Dr. McIntyre is the CEO of Braxia Scientific Corp. His coauthors’ disclosures are listed in the original paper. Dr. Price had received honoraria from AbbVie, Alkermes, Allergan, Intra-Cellular Therapies, Janssen, Jazz, Lundbeck, Neuronetics, Otsuka, and Supernus. Mr. Price and Dr. Cerimele reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Iloperidone, a second-generation antipsychotic used to treat schizophrenia, appears to be safe and effective in the treatment of bipolar mania, new research suggested.

Results of the phase 3 randomized double-blind placebo-controlled trial show patients with bipolar mania who received iloperidone had significantly greater change from baseline to 4 weeks on the Young Mania Rating Scale (YMRS) compared with placebo, an improvement detected as early as 14 days from the initial dose.

The incidence of akathisia and extrapyramidal symptoms (EPS) was low in the treatment group, and the medication was well-tolerated.

“This study provides evidence that iloperidone improves the symptoms of bipolar mania in adults and can be a useful treatment option for people with bipolar disorder,” the investigators, led by Rosarelis Torres, PhD, of Vanda Pharmaceuticals, and colleagues wrote.

The study was published online in the Journal of Clinical Psychiatry.
 

Early Improvement

Iloperidone was first approved by the US Food and Drug Administration in 2009 for treatment of schizophrenia.

The current study included 414 participants (mean age, 43 years; 56% male) across 17 US and international sites. Patients with psychotic features received a fixed daily dose of 24 mg of iloperidone (n = 206) or placebo (n = 208).

Participants completed a screening period of up to 7 days before randomization, followed by a 1-day baseline evaluation period and a 28-day treatment phase.

The primary efficacy endpoint was change from baseline to week 4 on the YMRS (vs placebo), while secondary efficacy endpoints included change from baseline on the Clinical Global Impressions-Severity and Clinical Global Impression of Change scales (CGI-S and CGI-C, respectively).

Compared with placebo, iloperidone was associated with significant improvement of mania symptoms at week 4, with a mean reduction on the YMRS scale of −4.0 (P = .000008), and significant decreases on the CGI-S (mean, −0.4; P = .0005) and CGI-C scales (mean, −0.5; P = .0002).

Statistically significant differences between iloperidone and placebo were observed as early as day 14 and continued through days 21 and 28.

Post hoc analyses found no difference in efficacy even when patients who had received benzodiazepines were excluded, regardless of the presence or absence of psychotic features at baseline.
 

Favorable Akathisia Profile

As for safety, 68% of patients in the iloperidone group experienced at least one adverse event, compared with 49% of patients in the placebo group.

Patients in the treatment group had a higher rate of withdrawal from the study than those in the placebo group (32.9% vs 27.1%), and more patients in the iloperidone group experienced treatment-emergent adverse events (TEAEs) leading to study drug discontinuation (8.7% vs 5.3%). However, no TEAEs associated with discontinuation occurred in more than two patients in either group, and none of the participants experienced any AE leading to death.

The most common adverse events (AEs) were tachycardia (18%), dizziness (11%), dry mouth (9%), increased alanine aminotransferase (7%), nasal congestion (6%), weight gain (6%), and somnolence (5%).

Five serious AEs were reported in four participants in the treatment group and one in the placebo group. Two were identified as related to the study medication. These included sedation and spontaneous penile erection.

Changes from baseline in clinical laboratory parameters were not largely different between the groups, but there were post-randomization changes in QT interval in three iloperidone patients. The incidence of orthostatic response was also higher for iloperidone vs placebo.

Although “much improved compared to early antipsychotics, SGAs can still cause considerable adverse motor side effects,” the authors wrote. “However, among all SGAs, iloperidone’s akathisia profile is favorable.”

Antipsychotic-induced akathisia has been reported more frequently in patients with bipolar disorder than in those with schizophrenia treated with the same medication, investigators noted.

One study limitation is the fact that long-term efficacy in the prevention of manic or depressive episodes was not assessed.
 

Potential Second-Line Treatment

Commenting on the study, Richard Louis Price, MD, assistant professor of psychiatry, at Weill Cornell Medical College, New York City, said the findings suggest iloperidone may be “modestly effective” for patients with bipolar 1 mania or mixed episodes.

“It’s helpful to have new treatment options, especially for patients who have difficulty tolerating other agents,” said Dr. Price, who was not involved with the study.

Also commenting on the research, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Toronto, Ontario, Canada, noted iloperidone’s “interesting antipsychotic pharmacodynamic,” highlighting the drug’s high-binding affinity for serotonin 5HT_2A and dopamine D₂ and D₃ receptors, as well as the noradrenergic α₁ receptors.

The drug’s profile “suggests benefit in manic features and agitation, perhaps with a lower propensity to EPS, which is especially important in persons at higher risk, like persons living with bipolar disorder,” Dr. McIntyre said.

Dr. McIntyre, who was not involved with the study, added iloperidone could be a second-line therapy because of its tolerability profile, provided the study results can be replicated.

“When considering alternatives with similar efficacy, absence of titration (or simple titration) minimal to no weight gain, no orthostatic hypotension, and no potential concerns with QT, those alternatives would have to be considered first-line, assuming that the study results are replicated,” he said.

This study was funded by Vanda Pharmaceuticals. The authors’ disclosures are listed in the original paper. Dr. McIntyre had received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine Biosciences, Sunovion, Bausch Health, Axsome Therapeutics, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular Therapies Inc., NewBridge Pharmaceuticals, Viatris, Abbvie, and Atai Life Sciences. McIntyre is the CEO of Braxia Scientific Corp. Dr. Price had received honoraria from AbbVie, Alkermes, Allergan, Intra-Cellular Therapies, Janssen, Jazz, Lundbeck, Neuronetics, Otsuka, and Supernus.

A version of this article appeared on Medscape.com.

Iloperidone, a second-generation antipsychotic used to treat schizophrenia, appears to be safe and effective in the treatment of bipolar mania, new research suggested.

Results of the phase 3 randomized double-blind placebo-controlled trial show patients with bipolar mania who received iloperidone had significantly greater change from baseline to 4 weeks on the Young Mania Rating Scale (YMRS) compared with placebo, an improvement detected as early as 14 days from the initial dose.

The incidence of akathisia and extrapyramidal symptoms (EPS) was low in the treatment group, and the medication was well-tolerated.

“This study provides evidence that iloperidone improves the symptoms of bipolar mania in adults and can be a useful treatment option for people with bipolar disorder,” the investigators, led by Rosarelis Torres, PhD, of Vanda Pharmaceuticals, and colleagues wrote.

The study was published online in the Journal of Clinical Psychiatry.
 

Early Improvement

Iloperidone was first approved by the US Food and Drug Administration in 2009 for treatment of schizophrenia.

The current study included 414 participants (mean age, 43 years; 56% male) across 17 US and international sites. Patients with psychotic features received a fixed daily dose of 24 mg of iloperidone (n = 206) or placebo (n = 208).

Participants completed a screening period of up to 7 days before randomization, followed by a 1-day baseline evaluation period and a 28-day treatment phase.

The primary efficacy endpoint was change from baseline to week 4 on the YMRS (vs placebo), while secondary efficacy endpoints included change from baseline on the Clinical Global Impressions-Severity and Clinical Global Impression of Change scales (CGI-S and CGI-C, respectively).

Compared with placebo, iloperidone was associated with significant improvement of mania symptoms at week 4, with a mean reduction on the YMRS scale of −4.0 (P = .000008), and significant decreases on the CGI-S (mean, −0.4; P = .0005) and CGI-C scales (mean, −0.5; P = .0002).

Statistically significant differences between iloperidone and placebo were observed as early as day 14 and continued through days 21 and 28.

Post hoc analyses found no difference in efficacy even when patients who had received benzodiazepines were excluded, regardless of the presence or absence of psychotic features at baseline.
 

Favorable Akathisia Profile

As for safety, 68% of patients in the iloperidone group experienced at least one adverse event, compared with 49% of patients in the placebo group.

Patients in the treatment group had a higher rate of withdrawal from the study than those in the placebo group (32.9% vs 27.1%), and more patients in the iloperidone group experienced treatment-emergent adverse events (TEAEs) leading to study drug discontinuation (8.7% vs 5.3%). However, no TEAEs associated with discontinuation occurred in more than two patients in either group, and none of the participants experienced any AE leading to death.

The most common adverse events (AEs) were tachycardia (18%), dizziness (11%), dry mouth (9%), increased alanine aminotransferase (7%), nasal congestion (6%), weight gain (6%), and somnolence (5%).

Five serious AEs were reported in four participants in the treatment group and one in the placebo group. Two were identified as related to the study medication. These included sedation and spontaneous penile erection.

Changes from baseline in clinical laboratory parameters were not largely different between the groups, but there were post-randomization changes in QT interval in three iloperidone patients. The incidence of orthostatic response was also higher for iloperidone vs placebo.

Although “much improved compared to early antipsychotics, SGAs can still cause considerable adverse motor side effects,” the authors wrote. “However, among all SGAs, iloperidone’s akathisia profile is favorable.”

Antipsychotic-induced akathisia has been reported more frequently in patients with bipolar disorder than in those with schizophrenia treated with the same medication, investigators noted.

One study limitation is the fact that long-term efficacy in the prevention of manic or depressive episodes was not assessed.
 

Potential Second-Line Treatment

Commenting on the study, Richard Louis Price, MD, assistant professor of psychiatry, at Weill Cornell Medical College, New York City, said the findings suggest iloperidone may be “modestly effective” for patients with bipolar 1 mania or mixed episodes.

“It’s helpful to have new treatment options, especially for patients who have difficulty tolerating other agents,” said Dr. Price, who was not involved with the study.

Also commenting on the research, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Toronto, Ontario, Canada, noted iloperidone’s “interesting antipsychotic pharmacodynamic,” highlighting the drug’s high-binding affinity for serotonin 5HT_2A and dopamine D₂ and D₃ receptors, as well as the noradrenergic α₁ receptors.

The drug’s profile “suggests benefit in manic features and agitation, perhaps with a lower propensity to EPS, which is especially important in persons at higher risk, like persons living with bipolar disorder,” Dr. McIntyre said.

Dr. McIntyre, who was not involved with the study, added iloperidone could be a second-line therapy because of its tolerability profile, provided the study results can be replicated.

“When considering alternatives with similar efficacy, absence of titration (or simple titration) minimal to no weight gain, no orthostatic hypotension, and no potential concerns with QT, those alternatives would have to be considered first-line, assuming that the study results are replicated,” he said.

This study was funded by Vanda Pharmaceuticals. The authors’ disclosures are listed in the original paper. Dr. McIntyre had received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine Biosciences, Sunovion, Bausch Health, Axsome Therapeutics, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular Therapies Inc., NewBridge Pharmaceuticals, Viatris, Abbvie, and Atai Life Sciences. McIntyre is the CEO of Braxia Scientific Corp. Dr. Price had received honoraria from AbbVie, Alkermes, Allergan, Intra-Cellular Therapies, Janssen, Jazz, Lundbeck, Neuronetics, Otsuka, and Supernus.

A version of this article appeared on Medscape.com.

Iloperidone, a second-generation antipsychotic used to treat schizophrenia, appears to be safe and effective in the treatment of bipolar mania, new research suggested.

Results of the phase 3 randomized double-blind placebo-controlled trial show patients with bipolar mania who received iloperidone had significantly greater change from baseline to 4 weeks on the Young Mania Rating Scale (YMRS) compared with placebo, an improvement detected as early as 14 days from the initial dose.

The incidence of akathisia and extrapyramidal symptoms (EPS) was low in the treatment group, and the medication was well-tolerated.

“This study provides evidence that iloperidone improves the symptoms of bipolar mania in adults and can be a useful treatment option for people with bipolar disorder,” the investigators, led by Rosarelis Torres, PhD, of Vanda Pharmaceuticals, and colleagues wrote.

The study was published online in the Journal of Clinical Psychiatry.
 

Early Improvement

Iloperidone was first approved by the US Food and Drug Administration in 2009 for treatment of schizophrenia.

The current study included 414 participants (mean age, 43 years; 56% male) across 17 US and international sites. Patients with psychotic features received a fixed daily dose of 24 mg of iloperidone (n = 206) or placebo (n = 208).

Participants completed a screening period of up to 7 days before randomization, followed by a 1-day baseline evaluation period and a 28-day treatment phase.

The primary efficacy endpoint was change from baseline to week 4 on the YMRS (vs placebo), while secondary efficacy endpoints included change from baseline on the Clinical Global Impressions-Severity and Clinical Global Impression of Change scales (CGI-S and CGI-C, respectively).

Compared with placebo, iloperidone was associated with significant improvement of mania symptoms at week 4, with a mean reduction on the YMRS scale of −4.0 (P = .000008), and significant decreases on the CGI-S (mean, −0.4; P = .0005) and CGI-C scales (mean, −0.5; P = .0002).

Statistically significant differences between iloperidone and placebo were observed as early as day 14 and continued through days 21 and 28.

Post hoc analyses found no difference in efficacy even when patients who had received benzodiazepines were excluded, regardless of the presence or absence of psychotic features at baseline.
 

Favorable Akathisia Profile

As for safety, 68% of patients in the iloperidone group experienced at least one adverse event, compared with 49% of patients in the placebo group.

Patients in the treatment group had a higher rate of withdrawal from the study than those in the placebo group (32.9% vs 27.1%), and more patients in the iloperidone group experienced treatment-emergent adverse events (TEAEs) leading to study drug discontinuation (8.7% vs 5.3%). However, no TEAEs associated with discontinuation occurred in more than two patients in either group, and none of the participants experienced any AE leading to death.

The most common adverse events (AEs) were tachycardia (18%), dizziness (11%), dry mouth (9%), increased alanine aminotransferase (7%), nasal congestion (6%), weight gain (6%), and somnolence (5%).

Five serious AEs were reported in four participants in the treatment group and one in the placebo group. Two were identified as related to the study medication. These included sedation and spontaneous penile erection.

Changes from baseline in clinical laboratory parameters were not largely different between the groups, but there were post-randomization changes in QT interval in three iloperidone patients. The incidence of orthostatic response was also higher for iloperidone vs placebo.

Although “much improved compared to early antipsychotics, SGAs can still cause considerable adverse motor side effects,” the authors wrote. “However, among all SGAs, iloperidone’s akathisia profile is favorable.”

Antipsychotic-induced akathisia has been reported more frequently in patients with bipolar disorder than in those with schizophrenia treated with the same medication, investigators noted.

One study limitation is the fact that long-term efficacy in the prevention of manic or depressive episodes was not assessed.
 

Potential Second-Line Treatment

Commenting on the study, Richard Louis Price, MD, assistant professor of psychiatry, at Weill Cornell Medical College, New York City, said the findings suggest iloperidone may be “modestly effective” for patients with bipolar 1 mania or mixed episodes.

“It’s helpful to have new treatment options, especially for patients who have difficulty tolerating other agents,” said Dr. Price, who was not involved with the study.

Also commenting on the research, Roger S. McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Toronto, Ontario, Canada, noted iloperidone’s “interesting antipsychotic pharmacodynamic,” highlighting the drug’s high-binding affinity for serotonin 5HT_2A and dopamine D₂ and D₃ receptors, as well as the noradrenergic α₁ receptors.

The drug’s profile “suggests benefit in manic features and agitation, perhaps with a lower propensity to EPS, which is especially important in persons at higher risk, like persons living with bipolar disorder,” Dr. McIntyre said.

Dr. McIntyre, who was not involved with the study, added iloperidone could be a second-line therapy because of its tolerability profile, provided the study results can be replicated.

“When considering alternatives with similar efficacy, absence of titration (or simple titration) minimal to no weight gain, no orthostatic hypotension, and no potential concerns with QT, those alternatives would have to be considered first-line, assuming that the study results are replicated,” he said.

This study was funded by Vanda Pharmaceuticals. The authors’ disclosures are listed in the original paper. Dr. McIntyre had received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine Biosciences, Sunovion, Bausch Health, Axsome Therapeutics, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular Therapies Inc., NewBridge Pharmaceuticals, Viatris, Abbvie, and Atai Life Sciences. McIntyre is the CEO of Braxia Scientific Corp. Dr. Price had received honoraria from AbbVie, Alkermes, Allergan, Intra-Cellular Therapies, Janssen, Jazz, Lundbeck, Neuronetics, Otsuka, and Supernus.

A version of this article appeared on Medscape.com.

One dose of synthetic psilocybin in combination with psychotherapy significantly reduces treatment-resistant depression associated with bipolar II disorder (BDII), a small, nonrandomized clinical trial shows. However, the investigators and other outside experts warn these results should not be overinterpreted.

Three weeks after receiving psilocybin and psychotherapy, all 15 participants’ depression scores dropped by an average of 24 points. Twelve met criteria for response and 11 for remission.

This benefit lasted until the 12-week mark, with 12 participants (80%) meeting criteria for both response and remission. There were no reports of mixed or manic symptoms, psychotic symptoms, or suicidal ideation.

Given the study’s small, open-label design, the findings should be interpreted cautiously, but the investigators say the results are promising.

“The results we saw from this trial are encouraging and further support the clinical study of psychedelics in patients with treatment-resistant bipolar II,” lead investigator Scott T. Aaronson, MD, chief science officer of the Institute for Advanced Diagnostics and Therapeutics at Sheppard Pratt Health System in Baltimore, Maryland, remarked in a press release. “One participant compared the transformation she experienced to taking a deep breath after breathing through a straw for years.”

The findings were published online on December 6, 2023, in JAMA Psychiatry.

Underserved Population

Previous studies show that psilocybin is effective in reducing the symptoms of treatment-resistant depression, major depressive disorder, and anorexia nervosa, most with only mild to moderate adverse effects.

Individuals with bipolar disorder (BPD) have been excluded from psilocybin studies in the last two decades. Investigators attribute this to anecdotal evidence that psychedelics may result in manic episodes in patients with BPD, even though empirical evidence of those effects is limited.

This study included 15 participants (9 female; mean age, 37.8 years) with BDII who had experienced an episode for more than 3 months and failed at least two medications within the current episode.

Participants stopped all psychotropic medications at least 2 weeks prior to the trial and received 25 mg of synthetic COMP360 psilocybin in a controlled setting. Psychotherapy included three sessions before dosing, one during the 8-hour dosing day, and three integration sessions posttreatment.

Depression was measured with the Montgomery Ǻsberg Depression Rating Scale (MADRS) at six points during the 12-week study.

By week 3, all 15 participants had lower MADRS scores, with a mean decrease of 24 points (P < .001). Twelve participants met the response criteria of ≥ 50% reduction in MADRS scores, and 11 met the criteria for remission of a MADRS score of ≤ 10 (both P < .001).

MADRS scores at each posttreatment time point were significantly lower than they were at baseline and the improvement persisted at 12 weeks.

Participants were also monitored for mania and suicidality at various time points during the study, and no significant changes were found from baseline.

“As a first open-label foray into this underserved and treatment-resistant population, care should be taken not to overinterpret the findings,” the authors note, adding that the findings may not apply to patients with BDI or BDII in a mixed or hypomanic phase of their illness.

No Definitive Conclusion

In an accompanying editorial, David B. Yaden, PhD, Johns Hopkins University School of Medicine, Baltimore, Maryland, and colleagues write that the findings are “tantalizingly suggestive,” but ultimately say nothing definitive about the efficacy of psilocybin for BDII.

“The danger is that some individuals will see the large (yet uncontrolled) effect size and believe that a new treatment of bipolar II has been discovered that is substantially better than all other treatments, while neglecting to mention the lack of control condition and substantial psychosocial support included in the study,” Dr. Yaden and colleagues wrote.

They also cautioned that due to the study’s limitations, which include its small sample size and lack of a control group, “it is imperative that the large effect size before to after the study is not overinterpreted.”

However, Dr. Yaden and colleagues also characterized the safety data as “compelling,” noting the safety profile could affect exclusion criteria in future studies involving people with BPD.

“The results of the present study provide preliminary evidence that perhaps those with bipolar II can be safely included in study samples without undue risk of triggering hypomanic episodes,” they wrote. “It also suggests re-evaluation of the need to exclude individuals with mere family history of bipolar II, which several studies do.”

The study was funded by COMPASS Pathways, who provided the study drug. Dr. Aaronson reported grants and nonfinancial support (supply of drug) from COMPASS Pathways during the conduct of the study and personal fees from LivaNova, Neuronetics, Genomind, and Sage Therapeutics outside the submitted work. Other disclosures are noted in the original article.
 

A version of this article appeared on Medscape.com.

One dose of synthetic psilocybin in combination with psychotherapy significantly reduces treatment-resistant depression associated with bipolar II disorder (BDII), a small, nonrandomized clinical trial shows. However, the investigators and other outside experts warn these results should not be overinterpreted.

Three weeks after receiving psilocybin and psychotherapy, all 15 participants’ depression scores dropped by an average of 24 points. Twelve met criteria for response and 11 for remission.

This benefit lasted until the 12-week mark, with 12 participants (80%) meeting criteria for both response and remission. There were no reports of mixed or manic symptoms, psychotic symptoms, or suicidal ideation.

Given the study’s small, open-label design, the findings should be interpreted cautiously, but the investigators say the results are promising.

“The results we saw from this trial are encouraging and further support the clinical study of psychedelics in patients with treatment-resistant bipolar II,” lead investigator Scott T. Aaronson, MD, chief science officer of the Institute for Advanced Diagnostics and Therapeutics at Sheppard Pratt Health System in Baltimore, Maryland, remarked in a press release. “One participant compared the transformation she experienced to taking a deep breath after breathing through a straw for years.”

The findings were published online on December 6, 2023, in JAMA Psychiatry.

Underserved Population

Previous studies show that psilocybin is effective in reducing the symptoms of treatment-resistant depression, major depressive disorder, and anorexia nervosa, most with only mild to moderate adverse effects.

Individuals with bipolar disorder (BPD) have been excluded from psilocybin studies in the last two decades. Investigators attribute this to anecdotal evidence that psychedelics may result in manic episodes in patients with BPD, even though empirical evidence of those effects is limited.

This study included 15 participants (9 female; mean age, 37.8 years) with BDII who had experienced an episode for more than 3 months and failed at least two medications within the current episode.

Participants stopped all psychotropic medications at least 2 weeks prior to the trial and received 25 mg of synthetic COMP360 psilocybin in a controlled setting. Psychotherapy included three sessions before dosing, one during the 8-hour dosing day, and three integration sessions posttreatment.

Depression was measured with the Montgomery Ǻsberg Depression Rating Scale (MADRS) at six points during the 12-week study.

By week 3, all 15 participants had lower MADRS scores, with a mean decrease of 24 points (P < .001). Twelve participants met the response criteria of ≥ 50% reduction in MADRS scores, and 11 met the criteria for remission of a MADRS score of ≤ 10 (both P < .001).

MADRS scores at each posttreatment time point were significantly lower than they were at baseline and the improvement persisted at 12 weeks.

Participants were also monitored for mania and suicidality at various time points during the study, and no significant changes were found from baseline.

“As a first open-label foray into this underserved and treatment-resistant population, care should be taken not to overinterpret the findings,” the authors note, adding that the findings may not apply to patients with BDI or BDII in a mixed or hypomanic phase of their illness.

No Definitive Conclusion

In an accompanying editorial, David B. Yaden, PhD, Johns Hopkins University School of Medicine, Baltimore, Maryland, and colleagues write that the findings are “tantalizingly suggestive,” but ultimately say nothing definitive about the efficacy of psilocybin for BDII.

“The danger is that some individuals will see the large (yet uncontrolled) effect size and believe that a new treatment of bipolar II has been discovered that is substantially better than all other treatments, while neglecting to mention the lack of control condition and substantial psychosocial support included in the study,” Dr. Yaden and colleagues wrote.

They also cautioned that due to the study’s limitations, which include its small sample size and lack of a control group, “it is imperative that the large effect size before to after the study is not overinterpreted.”

However, Dr. Yaden and colleagues also characterized the safety data as “compelling,” noting the safety profile could affect exclusion criteria in future studies involving people with BPD.

“The results of the present study provide preliminary evidence that perhaps those with bipolar II can be safely included in study samples without undue risk of triggering hypomanic episodes,” they wrote. “It also suggests re-evaluation of the need to exclude individuals with mere family history of bipolar II, which several studies do.”

The study was funded by COMPASS Pathways, who provided the study drug. Dr. Aaronson reported grants and nonfinancial support (supply of drug) from COMPASS Pathways during the conduct of the study and personal fees from LivaNova, Neuronetics, Genomind, and Sage Therapeutics outside the submitted work. Other disclosures are noted in the original article.
 

A version of this article appeared on Medscape.com.

One dose of synthetic psilocybin in combination with psychotherapy significantly reduces treatment-resistant depression associated with bipolar II disorder (BDII), a small, nonrandomized clinical trial shows. However, the investigators and other outside experts warn these results should not be overinterpreted.

Three weeks after receiving psilocybin and psychotherapy, all 15 participants’ depression scores dropped by an average of 24 points. Twelve met criteria for response and 11 for remission.

This benefit lasted until the 12-week mark, with 12 participants (80%) meeting criteria for both response and remission. There were no reports of mixed or manic symptoms, psychotic symptoms, or suicidal ideation.

Given the study’s small, open-label design, the findings should be interpreted cautiously, but the investigators say the results are promising.

“The results we saw from this trial are encouraging and further support the clinical study of psychedelics in patients with treatment-resistant bipolar II,” lead investigator Scott T. Aaronson, MD, chief science officer of the Institute for Advanced Diagnostics and Therapeutics at Sheppard Pratt Health System in Baltimore, Maryland, remarked in a press release. “One participant compared the transformation she experienced to taking a deep breath after breathing through a straw for years.”

The findings were published online on December 6, 2023, in JAMA Psychiatry.

Underserved Population

Previous studies show that psilocybin is effective in reducing the symptoms of treatment-resistant depression, major depressive disorder, and anorexia nervosa, most with only mild to moderate adverse effects.

Individuals with bipolar disorder (BPD) have been excluded from psilocybin studies in the last two decades. Investigators attribute this to anecdotal evidence that psychedelics may result in manic episodes in patients with BPD, even though empirical evidence of those effects is limited.

This study included 15 participants (9 female; mean age, 37.8 years) with BDII who had experienced an episode for more than 3 months and failed at least two medications within the current episode.

Participants stopped all psychotropic medications at least 2 weeks prior to the trial and received 25 mg of synthetic COMP360 psilocybin in a controlled setting. Psychotherapy included three sessions before dosing, one during the 8-hour dosing day, and three integration sessions posttreatment.

Depression was measured with the Montgomery Ǻsberg Depression Rating Scale (MADRS) at six points during the 12-week study.

By week 3, all 15 participants had lower MADRS scores, with a mean decrease of 24 points (P < .001). Twelve participants met the response criteria of ≥ 50% reduction in MADRS scores, and 11 met the criteria for remission of a MADRS score of ≤ 10 (both P < .001).

MADRS scores at each posttreatment time point were significantly lower than they were at baseline and the improvement persisted at 12 weeks.

Participants were also monitored for mania and suicidality at various time points during the study, and no significant changes were found from baseline.

“As a first open-label foray into this underserved and treatment-resistant population, care should be taken not to overinterpret the findings,” the authors note, adding that the findings may not apply to patients with BDI or BDII in a mixed or hypomanic phase of their illness.

No Definitive Conclusion

In an accompanying editorial, David B. Yaden, PhD, Johns Hopkins University School of Medicine, Baltimore, Maryland, and colleagues write that the findings are “tantalizingly suggestive,” but ultimately say nothing definitive about the efficacy of psilocybin for BDII.

“The danger is that some individuals will see the large (yet uncontrolled) effect size and believe that a new treatment of bipolar II has been discovered that is substantially better than all other treatments, while neglecting to mention the lack of control condition and substantial psychosocial support included in the study,” Dr. Yaden and colleagues wrote.

They also cautioned that due to the study’s limitations, which include its small sample size and lack of a control group, “it is imperative that the large effect size before to after the study is not overinterpreted.”

However, Dr. Yaden and colleagues also characterized the safety data as “compelling,” noting the safety profile could affect exclusion criteria in future studies involving people with BPD.

“The results of the present study provide preliminary evidence that perhaps those with bipolar II can be safely included in study samples without undue risk of triggering hypomanic episodes,” they wrote. “It also suggests re-evaluation of the need to exclude individuals with mere family history of bipolar II, which several studies do.”

The study was funded by COMPASS Pathways, who provided the study drug. Dr. Aaronson reported grants and nonfinancial support (supply of drug) from COMPASS Pathways during the conduct of the study and personal fees from LivaNova, Neuronetics, Genomind, and Sage Therapeutics outside the submitted work. Other disclosures are noted in the original article.
 

A version of this article appeared on Medscape.com.

For the last 30 years, the Center for Women’s Mental Health at Massachusetts General Hospital (MGH) has had as part of its mission, the conveying of accurate information about the reproductive safety of psychiatric medications. There has been a spectrum of medicines developed across psychiatric indications over the last several decades, and many studies over those decades have attempted to delineate the reproductive safety of these agents.

With the development of new antidepressants and second-generation antipsychotics has come an appreciation of the utility of these agents across a wide range of psychiatric disease states and psychiatric symptoms. More and more data demonstrate the efficacy of these medicines for mood and anxiety disorders; these agents are also used for a broad array of symptoms from insomnia, irritability, and symptoms of posttraumatic stress disorder (PTSD) just as examples — even absent formal approval by the US Food and Drug Administration (FDA) for these specific indications. With the growing use of medicines, including new antidepressants like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors, and second-generation atypical antipsychotics, there has been a greater interest and appreciation of the need to provide women with the best information about reproductive safety of these medicines as well.

When I began working in reproductive psychiatry, the FDA was using the pregnancy labeling categories introduced in 1979. The categories were simple, but also oversimplified in terms of incompletely conveying information about reproductive safety. For instance, category labels of B and C under the old labeling system could be nebulous, containing sparse information (in the case of category B) or animal data and some conflicting human data (in the case of category C) that may not have translated into relevant or easily interpretable safety information for patients and clinicians.

It was on that basis the current Pregnancy and Lactation Labeling (PLLR) Final Rule was published in 2014, which was a shift from categorical labeling to more descriptive labeling, including updated actual information on the package insert about available reproductive safety data, animal data, and data on lactation.

Even following the publication of the PLLR, there has still been an acknowledgment in the field that our assessment tools for postmarketing reproductive safety surveillance are incomplete. A recent 2-day FDA workshop hosted by the Duke-Margolis Center for Health Policy on optimizing the use of postapproval pregnancy safety studies sought to discuss the many questions that still surround this issue. Based on presentations at this workshop, a framework emerged for the future of assessing the reproductive safety of medications, which included an effort to develop the most effective model using tools such as pregnancy registries and harnessing “big data,” whether through electronic health records or large administrative databases from public and private insurers. Together, these various sources of information can provide signals of potential concern, prompting the need for a more rigorous look at the reproductive safety of a medication, or provide reassurance if data fail to indicate the absence of a signal of risk.

FDA’s new commitments under the latest reauthorization of the Prescription Drug User Fee Act (PDUFA VII) include pregnancy-specific postmarketing safety requirements as well as the creation of a framework for how data from pregnancy-specific postmarketing studies can be used. The agency is also conducting demonstration projects, including one for assessing the performance of pregnancy registries for the potential to detect safety signals for medications early in pregnancy. FDA is expanding its Sentinel Initiative to help accomplish these aims, and is implementing an Active Risk Identification and Analysis (ARIA) system to conduct active safety surveillance of medications used during pregnancy.

Pregnancy registries have now been available for decades, and some have been more successful than others across different classes of medicines, with the most rigorous registries including prospective follow-up of women across pregnancies and careful documentation of malformations (at best with original source data and with a blinded dysmorphologist). Still, with all of its rigor, even the best-intentioned efforts with respect to pregnancy registries have limitations. As I mentioned in my testimony during the public comment portion of the workshop, the sheer volume of pregnancy data from administrative databases we now have access to is attractive, but the quality of these data needs to be good enough to ascertain a signal of risk if they are to be used as a basis for reproductive safety determination.

The flip side of using data from large administrative databases is using carefully collected data from pregnancy registries. With a pregnancy registry, accrual of a substantial number of participants can also take a considerable period of time, and initial risk estimates of outcomes can have typically large confidence intervals, which can make it difficult to discern whether a drug is safe for women of reproductive age.

Another key issue is a lack of participation from manufacturers with respect to commitment to collection of high-quality reproductive safety data. History has shown that many medication manufacturers, unless required to have a dedicated registry as part of a postmarketing requirement or commitment, will invest sparse resources to track data on safety of fetal drug exposure. Participation is typically voluntary and varies from company to company unless, as noted previously, there is a postmarketing requirement or commitment tied to the approval of a medication. Just as a recent concrete example, the manufacturer of a new medication recently approved by the FDA for the treatment of postpartum depression (which will include presumably sexually active women well into the first postpartum year) has no plan to support the collection of reproductive safety data on this new medication because it is not required to, based on current FDA guidelines and the absence of a postmarketing requirement to do so.
 

Looking ahead

While the PLLR was a huge step forward in the field from the old pregnancy category system that could misinform women contemplating pregnancy, it also sets the stage for the next iteration of a system that allows us to generate information more quickly about the reproductive safety of medications. In psychiatry, as many as 10% of women use SSRIs during pregnancy. With drugs like atypical antipsychotics being used across disease states — in schizophrenia, bipolar disorder, depression, anxiety, insomnia, and PTSD — and where new classes of medicine are becoming available, like with ketamine or steroids, we need to have a system by which we can more quickly ascertain reproductive safety information. This information informs treatment decisions during a critical life event of deciding to try to become pregnant or during an actual pregnancy.

In my mind, it is reassuring when a registry has even as few as 50-60 cases of fetal exposure without an increase in the risk for malformation, because it can mean we are not seeing a repeat of the past with medications like thalidomide and sodium valproate. However, patients and clinicians are starved for better data. Risk assessment is also different from clinician to clinician and patient to patient. We want to empower patients to make decisions that work for them based on more rapidly accumulating information and help inform their decisions.

To come out on the “other side” of the PLLR, we will need to find a way to accelerate our ability to identify signals of risk or information that is reassuring (or not reassuring) so that clinicians and patients are not left waiting for the next paper to come out, which can be confusing when study results frequently conflict. I believe we have an obligation today to do this better, because the areas of reproductive toxicology and pharmacovigilance are growing incredibly quickly, and clinicians and patients are seeing these volumes of data being published without the ability to integrate that information in a systematic way.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

For the last 30 years, the Center for Women’s Mental Health at Massachusetts General Hospital (MGH) has had as part of its mission, the conveying of accurate information about the reproductive safety of psychiatric medications. There has been a spectrum of medicines developed across psychiatric indications over the last several decades, and many studies over those decades have attempted to delineate the reproductive safety of these agents.

With the development of new antidepressants and second-generation antipsychotics has come an appreciation of the utility of these agents across a wide range of psychiatric disease states and psychiatric symptoms. More and more data demonstrate the efficacy of these medicines for mood and anxiety disorders; these agents are also used for a broad array of symptoms from insomnia, irritability, and symptoms of posttraumatic stress disorder (PTSD) just as examples — even absent formal approval by the US Food and Drug Administration (FDA) for these specific indications. With the growing use of medicines, including new antidepressants like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors, and second-generation atypical antipsychotics, there has been a greater interest and appreciation of the need to provide women with the best information about reproductive safety of these medicines as well.

When I began working in reproductive psychiatry, the FDA was using the pregnancy labeling categories introduced in 1979. The categories were simple, but also oversimplified in terms of incompletely conveying information about reproductive safety. For instance, category labels of B and C under the old labeling system could be nebulous, containing sparse information (in the case of category B) or animal data and some conflicting human data (in the case of category C) that may not have translated into relevant or easily interpretable safety information for patients and clinicians.

It was on that basis the current Pregnancy and Lactation Labeling (PLLR) Final Rule was published in 2014, which was a shift from categorical labeling to more descriptive labeling, including updated actual information on the package insert about available reproductive safety data, animal data, and data on lactation.

Even following the publication of the PLLR, there has still been an acknowledgment in the field that our assessment tools for postmarketing reproductive safety surveillance are incomplete. A recent 2-day FDA workshop hosted by the Duke-Margolis Center for Health Policy on optimizing the use of postapproval pregnancy safety studies sought to discuss the many questions that still surround this issue. Based on presentations at this workshop, a framework emerged for the future of assessing the reproductive safety of medications, which included an effort to develop the most effective model using tools such as pregnancy registries and harnessing “big data,” whether through electronic health records or large administrative databases from public and private insurers. Together, these various sources of information can provide signals of potential concern, prompting the need for a more rigorous look at the reproductive safety of a medication, or provide reassurance if data fail to indicate the absence of a signal of risk.

FDA’s new commitments under the latest reauthorization of the Prescription Drug User Fee Act (PDUFA VII) include pregnancy-specific postmarketing safety requirements as well as the creation of a framework for how data from pregnancy-specific postmarketing studies can be used. The agency is also conducting demonstration projects, including one for assessing the performance of pregnancy registries for the potential to detect safety signals for medications early in pregnancy. FDA is expanding its Sentinel Initiative to help accomplish these aims, and is implementing an Active Risk Identification and Analysis (ARIA) system to conduct active safety surveillance of medications used during pregnancy.

Pregnancy registries have now been available for decades, and some have been more successful than others across different classes of medicines, with the most rigorous registries including prospective follow-up of women across pregnancies and careful documentation of malformations (at best with original source data and with a blinded dysmorphologist). Still, with all of its rigor, even the best-intentioned efforts with respect to pregnancy registries have limitations. As I mentioned in my testimony during the public comment portion of the workshop, the sheer volume of pregnancy data from administrative databases we now have access to is attractive, but the quality of these data needs to be good enough to ascertain a signal of risk if they are to be used as a basis for reproductive safety determination.

The flip side of using data from large administrative databases is using carefully collected data from pregnancy registries. With a pregnancy registry, accrual of a substantial number of participants can also take a considerable period of time, and initial risk estimates of outcomes can have typically large confidence intervals, which can make it difficult to discern whether a drug is safe for women of reproductive age.

Another key issue is a lack of participation from manufacturers with respect to commitment to collection of high-quality reproductive safety data. History has shown that many medication manufacturers, unless required to have a dedicated registry as part of a postmarketing requirement or commitment, will invest sparse resources to track data on safety of fetal drug exposure. Participation is typically voluntary and varies from company to company unless, as noted previously, there is a postmarketing requirement or commitment tied to the approval of a medication. Just as a recent concrete example, the manufacturer of a new medication recently approved by the FDA for the treatment of postpartum depression (which will include presumably sexually active women well into the first postpartum year) has no plan to support the collection of reproductive safety data on this new medication because it is not required to, based on current FDA guidelines and the absence of a postmarketing requirement to do so.
 

Looking ahead

While the PLLR was a huge step forward in the field from the old pregnancy category system that could misinform women contemplating pregnancy, it also sets the stage for the next iteration of a system that allows us to generate information more quickly about the reproductive safety of medications. In psychiatry, as many as 10% of women use SSRIs during pregnancy. With drugs like atypical antipsychotics being used across disease states — in schizophrenia, bipolar disorder, depression, anxiety, insomnia, and PTSD — and where new classes of medicine are becoming available, like with ketamine or steroids, we need to have a system by which we can more quickly ascertain reproductive safety information. This information informs treatment decisions during a critical life event of deciding to try to become pregnant or during an actual pregnancy.

In my mind, it is reassuring when a registry has even as few as 50-60 cases of fetal exposure without an increase in the risk for malformation, because it can mean we are not seeing a repeat of the past with medications like thalidomide and sodium valproate. However, patients and clinicians are starved for better data. Risk assessment is also different from clinician to clinician and patient to patient. We want to empower patients to make decisions that work for them based on more rapidly accumulating information and help inform their decisions.

To come out on the “other side” of the PLLR, we will need to find a way to accelerate our ability to identify signals of risk or information that is reassuring (or not reassuring) so that clinicians and patients are not left waiting for the next paper to come out, which can be confusing when study results frequently conflict. I believe we have an obligation today to do this better, because the areas of reproductive toxicology and pharmacovigilance are growing incredibly quickly, and clinicians and patients are seeing these volumes of data being published without the ability to integrate that information in a systematic way.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

For the last 30 years, the Center for Women’s Mental Health at Massachusetts General Hospital (MGH) has had as part of its mission, the conveying of accurate information about the reproductive safety of psychiatric medications. There has been a spectrum of medicines developed across psychiatric indications over the last several decades, and many studies over those decades have attempted to delineate the reproductive safety of these agents.

With the development of new antidepressants and second-generation antipsychotics has come an appreciation of the utility of these agents across a wide range of psychiatric disease states and psychiatric symptoms. More and more data demonstrate the efficacy of these medicines for mood and anxiety disorders; these agents are also used for a broad array of symptoms from insomnia, irritability, and symptoms of posttraumatic stress disorder (PTSD) just as examples — even absent formal approval by the US Food and Drug Administration (FDA) for these specific indications. With the growing use of medicines, including new antidepressants like selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors, and second-generation atypical antipsychotics, there has been a greater interest and appreciation of the need to provide women with the best information about reproductive safety of these medicines as well.

When I began working in reproductive psychiatry, the FDA was using the pregnancy labeling categories introduced in 1979. The categories were simple, but also oversimplified in terms of incompletely conveying information about reproductive safety. For instance, category labels of B and C under the old labeling system could be nebulous, containing sparse information (in the case of category B) or animal data and some conflicting human data (in the case of category C) that may not have translated into relevant or easily interpretable safety information for patients and clinicians.

It was on that basis the current Pregnancy and Lactation Labeling (PLLR) Final Rule was published in 2014, which was a shift from categorical labeling to more descriptive labeling, including updated actual information on the package insert about available reproductive safety data, animal data, and data on lactation.

Even following the publication of the PLLR, there has still been an acknowledgment in the field that our assessment tools for postmarketing reproductive safety surveillance are incomplete. A recent 2-day FDA workshop hosted by the Duke-Margolis Center for Health Policy on optimizing the use of postapproval pregnancy safety studies sought to discuss the many questions that still surround this issue. Based on presentations at this workshop, a framework emerged for the future of assessing the reproductive safety of medications, which included an effort to develop the most effective model using tools such as pregnancy registries and harnessing “big data,” whether through electronic health records or large administrative databases from public and private insurers. Together, these various sources of information can provide signals of potential concern, prompting the need for a more rigorous look at the reproductive safety of a medication, or provide reassurance if data fail to indicate the absence of a signal of risk.

FDA’s new commitments under the latest reauthorization of the Prescription Drug User Fee Act (PDUFA VII) include pregnancy-specific postmarketing safety requirements as well as the creation of a framework for how data from pregnancy-specific postmarketing studies can be used. The agency is also conducting demonstration projects, including one for assessing the performance of pregnancy registries for the potential to detect safety signals for medications early in pregnancy. FDA is expanding its Sentinel Initiative to help accomplish these aims, and is implementing an Active Risk Identification and Analysis (ARIA) system to conduct active safety surveillance of medications used during pregnancy.

Pregnancy registries have now been available for decades, and some have been more successful than others across different classes of medicines, with the most rigorous registries including prospective follow-up of women across pregnancies and careful documentation of malformations (at best with original source data and with a blinded dysmorphologist). Still, with all of its rigor, even the best-intentioned efforts with respect to pregnancy registries have limitations. As I mentioned in my testimony during the public comment portion of the workshop, the sheer volume of pregnancy data from administrative databases we now have access to is attractive, but the quality of these data needs to be good enough to ascertain a signal of risk if they are to be used as a basis for reproductive safety determination.

The flip side of using data from large administrative databases is using carefully collected data from pregnancy registries. With a pregnancy registry, accrual of a substantial number of participants can also take a considerable period of time, and initial risk estimates of outcomes can have typically large confidence intervals, which can make it difficult to discern whether a drug is safe for women of reproductive age.

Another key issue is a lack of participation from manufacturers with respect to commitment to collection of high-quality reproductive safety data. History has shown that many medication manufacturers, unless required to have a dedicated registry as part of a postmarketing requirement or commitment, will invest sparse resources to track data on safety of fetal drug exposure. Participation is typically voluntary and varies from company to company unless, as noted previously, there is a postmarketing requirement or commitment tied to the approval of a medication. Just as a recent concrete example, the manufacturer of a new medication recently approved by the FDA for the treatment of postpartum depression (which will include presumably sexually active women well into the first postpartum year) has no plan to support the collection of reproductive safety data on this new medication because it is not required to, based on current FDA guidelines and the absence of a postmarketing requirement to do so.
 

Looking ahead

While the PLLR was a huge step forward in the field from the old pregnancy category system that could misinform women contemplating pregnancy, it also sets the stage for the next iteration of a system that allows us to generate information more quickly about the reproductive safety of medications. In psychiatry, as many as 10% of women use SSRIs during pregnancy. With drugs like atypical antipsychotics being used across disease states — in schizophrenia, bipolar disorder, depression, anxiety, insomnia, and PTSD — and where new classes of medicine are becoming available, like with ketamine or steroids, we need to have a system by which we can more quickly ascertain reproductive safety information. This information informs treatment decisions during a critical life event of deciding to try to become pregnant or during an actual pregnancy.

In my mind, it is reassuring when a registry has even as few as 50-60 cases of fetal exposure without an increase in the risk for malformation, because it can mean we are not seeing a repeat of the past with medications like thalidomide and sodium valproate. However, patients and clinicians are starved for better data. Risk assessment is also different from clinician to clinician and patient to patient. We want to empower patients to make decisions that work for them based on more rapidly accumulating information and help inform their decisions.

To come out on the “other side” of the PLLR, we will need to find a way to accelerate our ability to identify signals of risk or information that is reassuring (or not reassuring) so that clinicians and patients are not left waiting for the next paper to come out, which can be confusing when study results frequently conflict. I believe we have an obligation today to do this better, because the areas of reproductive toxicology and pharmacovigilance are growing incredibly quickly, and clinicians and patients are seeing these volumes of data being published without the ability to integrate that information in a systematic way.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

Difficult ethical situations can arise when treating perinatal women who have serious mental illness (SMI). Clinicians must consider ethical issues related to administering antipsychotic medications, the safety of breastfeeding, and concerns for child welfare. They need to carefully weigh the risks and benefits of each decision when treating perinatal women who have SMI. Ethical guidelines can help clinicians best support families in these situations.

In this article, we describe 2 cases of women with psychotic disorders who requested to breastfeed after delivering their child during an inpatient psychiatric hospitalization. The course of their hospitalizations illustrated common ethical questions and facilitated the creation of a framework to assist with complex decision-making regarding breastfeeding on inpatient psychiatric units.

CASE 1

Ms. C, age 41, is multigravida with a psychiatric history of chronic, severe schizoaffective disorder and lives in supportive housing. When Ms. C presents to the hospital in search of a rape kit, clinicians discover she is 22 weeks pregnant but has not received any prenatal care. Psychiatry is consulted because she is found to be intermittently agitated and endorses grandiose delusions. Ms. C requires involuntary hospitalization for decompensated psychosis because she refuses prenatal and psychiatric care. Because it has reassuring reproductive safety data,¹ olanzapine 5 mg/d is started. However, Ms. C experiences minimal improvement from a maximum dose of 20 mg/d. After 13 weeks on the psychiatry unit, she is transferred to obstetrics service for preeclampsia with severe features. Ms. C requires an urgent cesarean delivery at 37 weeks. Her baby boy is transferred to the neonatal intensive care unit (NICU) for transient tachypnea. After delivery and in consultation with psychiatry, the pediatrics team calls Child Protective Services (CPS) due to concern for neglect driven by Ms. C’s psychiatric condition. Ms. C visits the child with medical unit staff supervision in the NICU without consulting with the psychiatry service or CPS. On postpartum Day 2, Ms. C is transferred back to psychiatry for persistent psychosis.

On postpartum Day 3, Ms. C starts to produce breastmilk and requests to breastfeed. At this time, the multidisciplinary team determines she is not able to visit her child in the NICU due to psychiatric instability. No plan is developed to facilitate hand expression or pumping of breastmilk while Ms. C is on the psychiatric unit. The clinical teams discuss whether the benefits of breastfeeding and/or pumping breastmilk would outweigh the risks. CPS determines that Ms. C is unable to retain custody and places the child in kinship foster care while awaiting clinical improvement from her.

CASE 2

Ms. S, age 32, has a history of schizophrenia. She lives with her husband and parents. She is pregnant for the first time and has been receiving consistent prenatal care. Ms. S is brought to the hospital by her husband for bizarre behavior and paranoia after self-discontinuing risperidone 2 mg twice daily due to concern about the medication’s influence on her pregnancy. An ultrasound confirms she is 37 weeks pregnant. Psychiatry is consulted because Ms. S is internally preoccupied, delusional, and endorses auditory hallucinations. She requires involuntary hospitalization for decompensated psychosis. During admission, Ms. S experiences improvement of her psychiatric symptoms while receiving risperidone 2 mg twice daily, which she takes consistently after receiving extensive psychoeducation regarding its safety profile during pregnancy and lactation.

After 2 weeks on the psychiatry unit, Ms. S’s care team transfers her to the obstetrics service with one-to-one supervision. At 39 weeks gestation, she has a vaginal delivery without complications. Because there are no concerns about infant harm, obstetrics, pediatrics, and psychiatry coordinate care so the baby can room in with Ms. S, her husband, and a staff supervisor to facilitate bonding. Ms. S starts to lactate, wishes to breastfeed, and meets with lactation, pediatric, obstetric, and psychiatric specialists to discuss the risks and benefits of breastfeeding and pumping breastmilk. She pursues direct breastfeeding until the baby is discharged home with the husband at postpartum Day 2. CPS is not called because there are no concerns for parental abuse or neglect at the infant’s discharge.

On postpartum Day 2, the obstetrics service transfers Ms. S back to the psychiatric unit for further treatment of her paranoia. She wishes to pump breastmilk while hospitalized, so the treatment team supplies a breast pump, facilitates the storage of breastmilk, and coordinates supervision during pumping to reduce the ligature risk. Ms. S’s husband visits daily to transport the milk and feed the infant breastmilk and formula to meet its nutritional needs. Ms. S maintains psychiatric stability while breast pumping, and the team helps transition her to breastfeeding during visitation with her husband and infant until she is discharged home at 2 weeks postpartum.

Continue to: Approaching care with a relational ethics framework

A relational ethics framework was constructed to evaluate whether to support breastfeeding for both patients during their psychiatric hospitalizations. A relational ethics perspective is defined as “a moral responsibility within a context of human relations” [that] “recognizes the human interdependency and reciprocity within which personal autonomy is embedded.”² This framework values connectedness and commonality between various and even conflicting parties. In the setting of a clinician-patient relationship, health care decisions are made with consideration of the patient’s traditional beliefs, values, and principles rather than the application of impartial moral principles. For these complex cases, this framework was chosen to determine the safest possible outcome for both mother and child.

Risks/benefits of breastfeeding by patients who have SMI

There are several methods of breastfeeding, including direct breastfeeding and other ways of expressing breastmilk such as pumping or hand expression.³ Unlike other forms of feeding using breastmilk, direct breastfeeding has been extensively studied, has well-established medical and psychological benefits for newborns and mothers, and enhances long-term bonding.⁴ Compared with their counterparts who do not breastfeed, mothers who breastfeed have lower rates of unintended pregnancy, cardiovascular disease, postpartum bleeding, osteoporosis, and breast and ovarian cancer.⁵ Among its key psychological benefits, breastfeeding is associated with an increase in maternal self-efficacy and, in some research, has been shown to be associated with a decreased risk of postpartum depression and stress.Additionally, breastfed infants experience lower rates of childhood infection and obesity, and improved nutrition, cognitive development, and immune function.⁶ The American Academy of Pediatrics recognizes these benefits and recommends that women exclusively breastfeed for 6 months postpartum and continue to breastfeed for 2 years or beyond if mutually desired by the mother and child.⁷ Absolute contraindications to breastfeeding must be ruled out (eg, infant classic galactosemia; maternal use of illicit substances such as cocaine, opioids, or phencyclidine; maternal HIV infection, etc).

The risks of breastfeeding by patients who have SMI must also be considered. In severe situations, the infant can be exposed to a mother’s agitation secondary to psychosis.^8,9 The transmission of antipsychotic medication through breastmilk and associated adverse effects (eg, sedation, poor feeding, and extrapyramidal symptoms) are also potential risks and varies among different antipsychotic medications.^1,10 Therefore, when prescribing an antipsychotic for a patient with SMI who breastfeeds, it is crucial to consider the medication’s safety profile as well as other factors, such as the relative infant dose (the weight-adjusted [ie, mg/kg] percentage of the maternal dosage ingested by a fully breastfed infant) and the molecular characteristics of the medication.^10-12 Neonates should be routinely monitored for adverse effects, medication toxicity, and withdrawal symptoms, and care should be coordinated with the infant’s pediatrician. Certain antipsychotic medications, such as aripiprazole, may impact breastmilk production through the dopamine agonist’s interference of the prolactin reflex and anticholinergic properties.^11,13 For a patient with SMI, perhaps the most significant risk involves the time and resources needed for breastfeeding, which can interfere with sleep and psychiatric treatment and possibly further exacerbate psychiatric symptoms.^14-16 Additionally, breastfeeding difficulties or disruption can increase the risk of psychiatric symptoms and psychological distress.¹⁷ In Ms. C’s case, there was a delay in the baby latching as well as multiple medical and psychiatric factors that hindered the milk-ejection reflex to properly initiate; both of these factors rendered breastfeeding particularly difficult while Ms. C was on the inpatient psychiatry unit.¹⁷ In comparison, Ms. S was able to bond with her infant shortly after delivery, which facilitated the milk-ejection reflex and lactation.

Patients who wish to directly breastfeed but struggle to do so while tending to their acute psychiatric condition can benefit from expression of breastmilk that can be provided to the infant or discarded to facilitate breastfeeding in the future.¹⁸ While expression of breastmilk may not be as advantageous for infant health as direct breastfeeding due to the potential changes in breastmilk composition from collecting, storing, and heating, this option can be more protective than formula feeding and facilitate future breastfeeding.¹⁹ In these clinical scenarios, it is standard care to provide a hospital-grade breast pump to the patient, much like a continuous positive airway pressure machine is provided to patients with obstructive sleep apnea.²⁰ However, there is often considerable difficulty obtaining proper breastfeeding equipment and a lack of services devoted to perinatal care in general inpatient settings. Barriers to direct breastfeeding and pumping of breastmilk are highlighted in the Table.²¹

Limitations on breastfeeding on an inpatient unit

The limitations in care and restrictions placed on breastfeeding are more optimally addressed in a mother and baby unit (MBU). MBUs are specialized inpatient psychiatric units designed for mothers experiencing severe perinatal psychiatric difficulties. Unlike general psychiatric units, MBUs allow for joint, full-time admission of mothers and their infants. These units also include multidisciplinary staff who specialize in treating perinatal mental health issues as well as infant care and child development.²² Admission into an MBU is considered best practice for new mothers requiring treatment, particularly in the United Kingdom, Australia, and France, as it is well-recognized that the separation of mother and baby can be psychologically harmful.²³ In the UK, most patients admitted to an MBU showed significant improvement of their psychiatric symptoms and reported overall high satisfaction with care.^24,25 Patients who experience postpartum psychosis prefer MBUs over general psychiatric units because the latter often lack specialized perinatal support, appropriate visitor arrangements, and adequate time with their infant.^26-28

Continue to: The resistance to adopting MBUs in the United States...

The resistance to adopting MBUs in the United States has posed significant barriers in care for perinatal patients and has been attributed to financial barriers, medicolegal risk, staffing, and safety concerns.²⁹ Though currently there are no MBUs in the US, other specialized units have been created. A partial day hospitalization program created in 2000 in Rhode Island for mothers and infants revolutionized the psychiatric care experience for new mothers.³⁰ Since then, other institutions have significantly expanded their services to include perinatal psychiatry inpatient units, yet unlike MBUs, these units typically do not provide overnight rooming-in with infants.³¹ They have the necessary resources and facilities to accommodate the mother’s needs and maximize positive mother-infant interaction, while actively integrating the infant into the mother’s treatment. Breast pumping is treated as a necessary medical procedure and patients can easily access hospital-grade breast pumps with staff supervision. At one such perinatal psychiatric inpatient unit, high rates of treatment satisfaction and significant improvements in symptoms of depression, anxiety, active suicidal ideation, and overall functioning were observed at discharge.³² Therefore, it is crucial to incorporate strategies in general psychiatry units to improve perinatal care, acknowledging that most patients will not have access to these specialized units.²¹

A framework to approaching the relational ethics decisions

An interdisciplinary team used a relational ethics perspective to carefully analyze the risks and benefits of these complex cases. In Figure 1, we propose a framework for the relational ethics decisions of breastfeeding on general inpatient psychiatric units. In creating this framework, we considered principles of autonomy, beneficence, and nonmaleficence, along with the medical and logistical barriers to breastfeeding.

In Ms. C’s case, the team determined that the risks—which included disrupting the mother’s psychiatric treatment, exposing her to psychological harm due to increasing attachment before remanding the child to CPS custody, and risks to the child due to potential unpredictable agitation driven by the treatment-refractory psychosis of the mother as well as that of other psychiatric patients—outweighed the benefits of breastfeeding. We instead recommended breast pumping as an alternative once Ms. C’s psychiatric stability improved. We presented Ms. C with the option of breast pumping on postpartum Day 5. During a 1-day period in which she showed improved behavioral control, she was counseled on the risks and benefits of breastfeeding and exclusive pumping and was notified that the team would help her with the necessary resources, including consultation with a lactation specialist and breast pump. Despite lactation consultant support, Ms. C had low milk production and difficulty with hand expression, which was very discouraging to her. She produced 1 ounce of milk that was shared with the newborn while in the NICU. Because Ms. C’s psychiatric symptoms continued to be severe, with lability and aggression, and because pumping was triggering distress, the multidisciplinary team determined the best course of care would be to focus on her psychiatric recovery rather than on pumping breastmilk. To reduce milk production and minimize discomfort secondary to breast engorgement, the lactation consultant recommended cold compresses, pain management, and compression of breasts. Ultimately, the mother-infant dyad was unable to reap the benefits of breastfeeding (via pumping or direct breastfeeding) due to the mother’s underlying psychiatric illness, although the staffing, psychosocial support, and logistical limitations contributed to this outcome.³³

In Ms. S’s case, the treatment team determined that there were no medical or psychiatric contraindications to breastfeeding, and she was counseled on the risks and benefits of direct breastfeeding and pumping. The treatment team determined it was safe for Ms. S to directly breastfeed as there were no concerns for infant harm post­delivery with constant supervision while on the obstetrics floor. The patient opted to directly breastfeed, which was successful with the guidance of a lactation specialist. When she was transferred to the psychiatric unit on postpartum Day 2, her child was discharged home with the husband. The patient was then encouraged to pump while the psychiatrists monitored her symptoms closely and facilitated increased staff and resources. Transportation of breastmilk was made possible by the family, and on postpartum Day 5, as the patient maintained psychiatric stability, the team discussed with Ms. S and her husband the prospect of direct breastfeeding. The treatment team arranged for separate visitation hours to minimize the possibility of exposing the infant to aggression from other patients on the unit and advocated with hospital leadership to approve of infant visitation on the unit.

Impact of involvement of Child Protective Services

The involvement of CPS also added complexity to Ms. C’s case. Without proper legal guidance, mothers with psychosis who lose custody can find it difficult to navigate the legal system and maintain contact with their children.³⁴ As the prevalence of custody loss in mothers with psychosis is high (approximately 50% according to research published in the last 10 years), effective interventions to reunite the mother and child must be promoted (Figure 2).^35-39 Ultimately, the goal of psychiatric hospitalization for perinatal women who have SMI is psychiatric stabilization. The preemptive involvement of psychiatry is crucial because it can allow for early postpartum planning and can provide an opportunity to address feeding options and custody concerns with the patient, social supports and services, and various medical teams. In Ms. C’s case, she visited her baby in the NICU on postpartum Day 2 without consultation with psychiatry or CPS, which posed risks to the patient, infant, and staff. It is vital that various clinicians collaborate with each other and the patient, working towards the goal of optimizing the patient’s mental health to allow for parenting rights in the future and maximizing a sustainable attachment between the parent and child. In Ms. S’s case, the husband was able to facilitate caring for the baby while the mother was hospitalized and played an integral role in the feeding process via pumped breastmilk and transport of the infant for direct breastfeeding.

Continue to: The differences in these 2 cases...

The differences in these 2 cases show the extreme importance of social support to benefit both the mother and child, and the need for more comprehensive social services for women who do not have a social safety net.

Bottom Line

These complex cases highlight an ethical decision-making approach to breastfeeding in perinatal women who have serious mental illness. Collaborative care and shared decision-making, which highlight the interests of the mother and baby, are crucial when assessing the risks and benefits of breastfeeding and pumping breastmilk. Our relational ethics framework can be used to better evaluate and implement breastfeeding options on general psychiatric units.

Related Resources

• Tillman B, Sloan N, Westmoreland P. How COVID-19 affects peripartum women’s mental health. Current Psychiatry. 2021;20(6):18-22. doi:10.12788/cp.0129
• Koch J, Preinitz J. Antidepressants for patients who are breastfeeding: what to consider. Current Psychiatry. 2023;22(5):20-23,48. doi:10.12788/cp.0355

Drug Brand Names

Aripiprazole • Abilify
Olanzapine • Zyprexa
Risperidone • Risperdal

Difficult ethical situations can arise when treating perinatal women who have serious mental illness (SMI). Clinicians must consider ethical issues related to administering antipsychotic medications, the safety of breastfeeding, and concerns for child welfare. They need to carefully weigh the risks and benefits of each decision when treating perinatal women who have SMI. Ethical guidelines can help clinicians best support families in these situations.

In this article, we describe 2 cases of women with psychotic disorders who requested to breastfeed after delivering their child during an inpatient psychiatric hospitalization. The course of their hospitalizations illustrated common ethical questions and facilitated the creation of a framework to assist with complex decision-making regarding breastfeeding on inpatient psychiatric units.

CASE 1

Ms. C, age 41, is multigravida with a psychiatric history of chronic, severe schizoaffective disorder and lives in supportive housing. When Ms. C presents to the hospital in search of a rape kit, clinicians discover she is 22 weeks pregnant but has not received any prenatal care. Psychiatry is consulted because she is found to be intermittently agitated and endorses grandiose delusions. Ms. C requires involuntary hospitalization for decompensated psychosis because she refuses prenatal and psychiatric care. Because it has reassuring reproductive safety data,¹ olanzapine 5 mg/d is started. However, Ms. C experiences minimal improvement from a maximum dose of 20 mg/d. After 13 weeks on the psychiatry unit, she is transferred to obstetrics service for preeclampsia with severe features. Ms. C requires an urgent cesarean delivery at 37 weeks. Her baby boy is transferred to the neonatal intensive care unit (NICU) for transient tachypnea. After delivery and in consultation with psychiatry, the pediatrics team calls Child Protective Services (CPS) due to concern for neglect driven by Ms. C’s psychiatric condition. Ms. C visits the child with medical unit staff supervision in the NICU without consulting with the psychiatry service or CPS. On postpartum Day 2, Ms. C is transferred back to psychiatry for persistent psychosis.

On postpartum Day 3, Ms. C starts to produce breastmilk and requests to breastfeed. At this time, the multidisciplinary team determines she is not able to visit her child in the NICU due to psychiatric instability. No plan is developed to facilitate hand expression or pumping of breastmilk while Ms. C is on the psychiatric unit. The clinical teams discuss whether the benefits of breastfeeding and/or pumping breastmilk would outweigh the risks. CPS determines that Ms. C is unable to retain custody and places the child in kinship foster care while awaiting clinical improvement from her.

CASE 2

Ms. S, age 32, has a history of schizophrenia. She lives with her husband and parents. She is pregnant for the first time and has been receiving consistent prenatal care. Ms. S is brought to the hospital by her husband for bizarre behavior and paranoia after self-discontinuing risperidone 2 mg twice daily due to concern about the medication’s influence on her pregnancy. An ultrasound confirms she is 37 weeks pregnant. Psychiatry is consulted because Ms. S is internally preoccupied, delusional, and endorses auditory hallucinations. She requires involuntary hospitalization for decompensated psychosis. During admission, Ms. S experiences improvement of her psychiatric symptoms while receiving risperidone 2 mg twice daily, which she takes consistently after receiving extensive psychoeducation regarding its safety profile during pregnancy and lactation.

After 2 weeks on the psychiatry unit, Ms. S’s care team transfers her to the obstetrics service with one-to-one supervision. At 39 weeks gestation, she has a vaginal delivery without complications. Because there are no concerns about infant harm, obstetrics, pediatrics, and psychiatry coordinate care so the baby can room in with Ms. S, her husband, and a staff supervisor to facilitate bonding. Ms. S starts to lactate, wishes to breastfeed, and meets with lactation, pediatric, obstetric, and psychiatric specialists to discuss the risks and benefits of breastfeeding and pumping breastmilk. She pursues direct breastfeeding until the baby is discharged home with the husband at postpartum Day 2. CPS is not called because there are no concerns for parental abuse or neglect at the infant’s discharge.

On postpartum Day 2, the obstetrics service transfers Ms. S back to the psychiatric unit for further treatment of her paranoia. She wishes to pump breastmilk while hospitalized, so the treatment team supplies a breast pump, facilitates the storage of breastmilk, and coordinates supervision during pumping to reduce the ligature risk. Ms. S’s husband visits daily to transport the milk and feed the infant breastmilk and formula to meet its nutritional needs. Ms. S maintains psychiatric stability while breast pumping, and the team helps transition her to breastfeeding during visitation with her husband and infant until she is discharged home at 2 weeks postpartum.

Continue to: Approaching care with a relational ethics framework

A relational ethics framework was constructed to evaluate whether to support breastfeeding for both patients during their psychiatric hospitalizations. A relational ethics perspective is defined as “a moral responsibility within a context of human relations” [that] “recognizes the human interdependency and reciprocity within which personal autonomy is embedded.”² This framework values connectedness and commonality between various and even conflicting parties. In the setting of a clinician-patient relationship, health care decisions are made with consideration of the patient’s traditional beliefs, values, and principles rather than the application of impartial moral principles. For these complex cases, this framework was chosen to determine the safest possible outcome for both mother and child.

Risks/benefits of breastfeeding by patients who have SMI

There are several methods of breastfeeding, including direct breastfeeding and other ways of expressing breastmilk such as pumping or hand expression.³ Unlike other forms of feeding using breastmilk, direct breastfeeding has been extensively studied, has well-established medical and psychological benefits for newborns and mothers, and enhances long-term bonding.⁴ Compared with their counterparts who do not breastfeed, mothers who breastfeed have lower rates of unintended pregnancy, cardiovascular disease, postpartum bleeding, osteoporosis, and breast and ovarian cancer.⁵ Among its key psychological benefits, breastfeeding is associated with an increase in maternal self-efficacy and, in some research, has been shown to be associated with a decreased risk of postpartum depression and stress.Additionally, breastfed infants experience lower rates of childhood infection and obesity, and improved nutrition, cognitive development, and immune function.⁶ The American Academy of Pediatrics recognizes these benefits and recommends that women exclusively breastfeed for 6 months postpartum and continue to breastfeed for 2 years or beyond if mutually desired by the mother and child.⁷ Absolute contraindications to breastfeeding must be ruled out (eg, infant classic galactosemia; maternal use of illicit substances such as cocaine, opioids, or phencyclidine; maternal HIV infection, etc).

The risks of breastfeeding by patients who have SMI must also be considered. In severe situations, the infant can be exposed to a mother’s agitation secondary to psychosis.^8,9 The transmission of antipsychotic medication through breastmilk and associated adverse effects (eg, sedation, poor feeding, and extrapyramidal symptoms) are also potential risks and varies among different antipsychotic medications.^1,10 Therefore, when prescribing an antipsychotic for a patient with SMI who breastfeeds, it is crucial to consider the medication’s safety profile as well as other factors, such as the relative infant dose (the weight-adjusted [ie, mg/kg] percentage of the maternal dosage ingested by a fully breastfed infant) and the molecular characteristics of the medication.^10-12 Neonates should be routinely monitored for adverse effects, medication toxicity, and withdrawal symptoms, and care should be coordinated with the infant’s pediatrician. Certain antipsychotic medications, such as aripiprazole, may impact breastmilk production through the dopamine agonist’s interference of the prolactin reflex and anticholinergic properties.^11,13 For a patient with SMI, perhaps the most significant risk involves the time and resources needed for breastfeeding, which can interfere with sleep and psychiatric treatment and possibly further exacerbate psychiatric symptoms.^14-16 Additionally, breastfeeding difficulties or disruption can increase the risk of psychiatric symptoms and psychological distress.¹⁷ In Ms. C’s case, there was a delay in the baby latching as well as multiple medical and psychiatric factors that hindered the milk-ejection reflex to properly initiate; both of these factors rendered breastfeeding particularly difficult while Ms. C was on the inpatient psychiatry unit.¹⁷ In comparison, Ms. S was able to bond with her infant shortly after delivery, which facilitated the milk-ejection reflex and lactation.

Patients who wish to directly breastfeed but struggle to do so while tending to their acute psychiatric condition can benefit from expression of breastmilk that can be provided to the infant or discarded to facilitate breastfeeding in the future.¹⁸ While expression of breastmilk may not be as advantageous for infant health as direct breastfeeding due to the potential changes in breastmilk composition from collecting, storing, and heating, this option can be more protective than formula feeding and facilitate future breastfeeding.¹⁹ In these clinical scenarios, it is standard care to provide a hospital-grade breast pump to the patient, much like a continuous positive airway pressure machine is provided to patients with obstructive sleep apnea.²⁰ However, there is often considerable difficulty obtaining proper breastfeeding equipment and a lack of services devoted to perinatal care in general inpatient settings. Barriers to direct breastfeeding and pumping of breastmilk are highlighted in the Table.²¹

Limitations on breastfeeding on an inpatient unit

The limitations in care and restrictions placed on breastfeeding are more optimally addressed in a mother and baby unit (MBU). MBUs are specialized inpatient psychiatric units designed for mothers experiencing severe perinatal psychiatric difficulties. Unlike general psychiatric units, MBUs allow for joint, full-time admission of mothers and their infants. These units also include multidisciplinary staff who specialize in treating perinatal mental health issues as well as infant care and child development.²² Admission into an MBU is considered best practice for new mothers requiring treatment, particularly in the United Kingdom, Australia, and France, as it is well-recognized that the separation of mother and baby can be psychologically harmful.²³ In the UK, most patients admitted to an MBU showed significant improvement of their psychiatric symptoms and reported overall high satisfaction with care.^24,25 Patients who experience postpartum psychosis prefer MBUs over general psychiatric units because the latter often lack specialized perinatal support, appropriate visitor arrangements, and adequate time with their infant.^26-28

Continue to: The resistance to adopting MBUs in the United States...

The resistance to adopting MBUs in the United States has posed significant barriers in care for perinatal patients and has been attributed to financial barriers, medicolegal risk, staffing, and safety concerns.²⁹ Though currently there are no MBUs in the US, other specialized units have been created. A partial day hospitalization program created in 2000 in Rhode Island for mothers and infants revolutionized the psychiatric care experience for new mothers.³⁰ Since then, other institutions have significantly expanded their services to include perinatal psychiatry inpatient units, yet unlike MBUs, these units typically do not provide overnight rooming-in with infants.³¹ They have the necessary resources and facilities to accommodate the mother’s needs and maximize positive mother-infant interaction, while actively integrating the infant into the mother’s treatment. Breast pumping is treated as a necessary medical procedure and patients can easily access hospital-grade breast pumps with staff supervision. At one such perinatal psychiatric inpatient unit, high rates of treatment satisfaction and significant improvements in symptoms of depression, anxiety, active suicidal ideation, and overall functioning were observed at discharge.³² Therefore, it is crucial to incorporate strategies in general psychiatry units to improve perinatal care, acknowledging that most patients will not have access to these specialized units.²¹

A framework to approaching the relational ethics decisions

An interdisciplinary team used a relational ethics perspective to carefully analyze the risks and benefits of these complex cases. In Figure 1, we propose a framework for the relational ethics decisions of breastfeeding on general inpatient psychiatric units. In creating this framework, we considered principles of autonomy, beneficence, and nonmaleficence, along with the medical and logistical barriers to breastfeeding.

In Ms. C’s case, the team determined that the risks—which included disrupting the mother’s psychiatric treatment, exposing her to psychological harm due to increasing attachment before remanding the child to CPS custody, and risks to the child due to potential unpredictable agitation driven by the treatment-refractory psychosis of the mother as well as that of other psychiatric patients—outweighed the benefits of breastfeeding. We instead recommended breast pumping as an alternative once Ms. C’s psychiatric stability improved. We presented Ms. C with the option of breast pumping on postpartum Day 5. During a 1-day period in which she showed improved behavioral control, she was counseled on the risks and benefits of breastfeeding and exclusive pumping and was notified that the team would help her with the necessary resources, including consultation with a lactation specialist and breast pump. Despite lactation consultant support, Ms. C had low milk production and difficulty with hand expression, which was very discouraging to her. She produced 1 ounce of milk that was shared with the newborn while in the NICU. Because Ms. C’s psychiatric symptoms continued to be severe, with lability and aggression, and because pumping was triggering distress, the multidisciplinary team determined the best course of care would be to focus on her psychiatric recovery rather than on pumping breastmilk. To reduce milk production and minimize discomfort secondary to breast engorgement, the lactation consultant recommended cold compresses, pain management, and compression of breasts. Ultimately, the mother-infant dyad was unable to reap the benefits of breastfeeding (via pumping or direct breastfeeding) due to the mother’s underlying psychiatric illness, although the staffing, psychosocial support, and logistical limitations contributed to this outcome.³³

In Ms. S’s case, the treatment team determined that there were no medical or psychiatric contraindications to breastfeeding, and she was counseled on the risks and benefits of direct breastfeeding and pumping. The treatment team determined it was safe for Ms. S to directly breastfeed as there were no concerns for infant harm post­delivery with constant supervision while on the obstetrics floor. The patient opted to directly breastfeed, which was successful with the guidance of a lactation specialist. When she was transferred to the psychiatric unit on postpartum Day 2, her child was discharged home with the husband. The patient was then encouraged to pump while the psychiatrists monitored her symptoms closely and facilitated increased staff and resources. Transportation of breastmilk was made possible by the family, and on postpartum Day 5, as the patient maintained psychiatric stability, the team discussed with Ms. S and her husband the prospect of direct breastfeeding. The treatment team arranged for separate visitation hours to minimize the possibility of exposing the infant to aggression from other patients on the unit and advocated with hospital leadership to approve of infant visitation on the unit.

Impact of involvement of Child Protective Services

The involvement of CPS also added complexity to Ms. C’s case. Without proper legal guidance, mothers with psychosis who lose custody can find it difficult to navigate the legal system and maintain contact with their children.³⁴ As the prevalence of custody loss in mothers with psychosis is high (approximately 50% according to research published in the last 10 years), effective interventions to reunite the mother and child must be promoted (Figure 2).^35-39 Ultimately, the goal of psychiatric hospitalization for perinatal women who have SMI is psychiatric stabilization. The preemptive involvement of psychiatry is crucial because it can allow for early postpartum planning and can provide an opportunity to address feeding options and custody concerns with the patient, social supports and services, and various medical teams. In Ms. C’s case, she visited her baby in the NICU on postpartum Day 2 without consultation with psychiatry or CPS, which posed risks to the patient, infant, and staff. It is vital that various clinicians collaborate with each other and the patient, working towards the goal of optimizing the patient’s mental health to allow for parenting rights in the future and maximizing a sustainable attachment between the parent and child. In Ms. S’s case, the husband was able to facilitate caring for the baby while the mother was hospitalized and played an integral role in the feeding process via pumped breastmilk and transport of the infant for direct breastfeeding.

Continue to: The differences in these 2 cases...

The differences in these 2 cases show the extreme importance of social support to benefit both the mother and child, and the need for more comprehensive social services for women who do not have a social safety net.

Bottom Line

These complex cases highlight an ethical decision-making approach to breastfeeding in perinatal women who have serious mental illness. Collaborative care and shared decision-making, which highlight the interests of the mother and baby, are crucial when assessing the risks and benefits of breastfeeding and pumping breastmilk. Our relational ethics framework can be used to better evaluate and implement breastfeeding options on general psychiatric units.

Related Resources

• Tillman B, Sloan N, Westmoreland P. How COVID-19 affects peripartum women’s mental health. Current Psychiatry. 2021;20(6):18-22. doi:10.12788/cp.0129
• Koch J, Preinitz J. Antidepressants for patients who are breastfeeding: what to consider. Current Psychiatry. 2023;22(5):20-23,48. doi:10.12788/cp.0355

Drug Brand Names

Aripiprazole • Abilify
Olanzapine • Zyprexa
Risperidone • Risperdal

Difficult ethical situations can arise when treating perinatal women who have serious mental illness (SMI). Clinicians must consider ethical issues related to administering antipsychotic medications, the safety of breastfeeding, and concerns for child welfare. They need to carefully weigh the risks and benefits of each decision when treating perinatal women who have SMI. Ethical guidelines can help clinicians best support families in these situations.

In this article, we describe 2 cases of women with psychotic disorders who requested to breastfeed after delivering their child during an inpatient psychiatric hospitalization. The course of their hospitalizations illustrated common ethical questions and facilitated the creation of a framework to assist with complex decision-making regarding breastfeeding on inpatient psychiatric units.

CASE 1

Ms. C, age 41, is multigravida with a psychiatric history of chronic, severe schizoaffective disorder and lives in supportive housing. When Ms. C presents to the hospital in search of a rape kit, clinicians discover she is 22 weeks pregnant but has not received any prenatal care. Psychiatry is consulted because she is found to be intermittently agitated and endorses grandiose delusions. Ms. C requires involuntary hospitalization for decompensated psychosis because she refuses prenatal and psychiatric care. Because it has reassuring reproductive safety data,¹ olanzapine 5 mg/d is started. However, Ms. C experiences minimal improvement from a maximum dose of 20 mg/d. After 13 weeks on the psychiatry unit, she is transferred to obstetrics service for preeclampsia with severe features. Ms. C requires an urgent cesarean delivery at 37 weeks. Her baby boy is transferred to the neonatal intensive care unit (NICU) for transient tachypnea. After delivery and in consultation with psychiatry, the pediatrics team calls Child Protective Services (CPS) due to concern for neglect driven by Ms. C’s psychiatric condition. Ms. C visits the child with medical unit staff supervision in the NICU without consulting with the psychiatry service or CPS. On postpartum Day 2, Ms. C is transferred back to psychiatry for persistent psychosis.

On postpartum Day 3, Ms. C starts to produce breastmilk and requests to breastfeed. At this time, the multidisciplinary team determines she is not able to visit her child in the NICU due to psychiatric instability. No plan is developed to facilitate hand expression or pumping of breastmilk while Ms. C is on the psychiatric unit. The clinical teams discuss whether the benefits of breastfeeding and/or pumping breastmilk would outweigh the risks. CPS determines that Ms. C is unable to retain custody and places the child in kinship foster care while awaiting clinical improvement from her.

CASE 2

Ms. S, age 32, has a history of schizophrenia. She lives with her husband and parents. She is pregnant for the first time and has been receiving consistent prenatal care. Ms. S is brought to the hospital by her husband for bizarre behavior and paranoia after self-discontinuing risperidone 2 mg twice daily due to concern about the medication’s influence on her pregnancy. An ultrasound confirms she is 37 weeks pregnant. Psychiatry is consulted because Ms. S is internally preoccupied, delusional, and endorses auditory hallucinations. She requires involuntary hospitalization for decompensated psychosis. During admission, Ms. S experiences improvement of her psychiatric symptoms while receiving risperidone 2 mg twice daily, which she takes consistently after receiving extensive psychoeducation regarding its safety profile during pregnancy and lactation.

After 2 weeks on the psychiatry unit, Ms. S’s care team transfers her to the obstetrics service with one-to-one supervision. At 39 weeks gestation, she has a vaginal delivery without complications. Because there are no concerns about infant harm, obstetrics, pediatrics, and psychiatry coordinate care so the baby can room in with Ms. S, her husband, and a staff supervisor to facilitate bonding. Ms. S starts to lactate, wishes to breastfeed, and meets with lactation, pediatric, obstetric, and psychiatric specialists to discuss the risks and benefits of breastfeeding and pumping breastmilk. She pursues direct breastfeeding until the baby is discharged home with the husband at postpartum Day 2. CPS is not called because there are no concerns for parental abuse or neglect at the infant’s discharge.

On postpartum Day 2, the obstetrics service transfers Ms. S back to the psychiatric unit for further treatment of her paranoia. She wishes to pump breastmilk while hospitalized, so the treatment team supplies a breast pump, facilitates the storage of breastmilk, and coordinates supervision during pumping to reduce the ligature risk. Ms. S’s husband visits daily to transport the milk and feed the infant breastmilk and formula to meet its nutritional needs. Ms. S maintains psychiatric stability while breast pumping, and the team helps transition her to breastfeeding during visitation with her husband and infant until she is discharged home at 2 weeks postpartum.

Continue to: Approaching care with a relational ethics framework

A relational ethics framework was constructed to evaluate whether to support breastfeeding for both patients during their psychiatric hospitalizations. A relational ethics perspective is defined as “a moral responsibility within a context of human relations” [that] “recognizes the human interdependency and reciprocity within which personal autonomy is embedded.”² This framework values connectedness and commonality between various and even conflicting parties. In the setting of a clinician-patient relationship, health care decisions are made with consideration of the patient’s traditional beliefs, values, and principles rather than the application of impartial moral principles. For these complex cases, this framework was chosen to determine the safest possible outcome for both mother and child.

Risks/benefits of breastfeeding by patients who have SMI

There are several methods of breastfeeding, including direct breastfeeding and other ways of expressing breastmilk such as pumping or hand expression.³ Unlike other forms of feeding using breastmilk, direct breastfeeding has been extensively studied, has well-established medical and psychological benefits for newborns and mothers, and enhances long-term bonding.⁴ Compared with their counterparts who do not breastfeed, mothers who breastfeed have lower rates of unintended pregnancy, cardiovascular disease, postpartum bleeding, osteoporosis, and breast and ovarian cancer.⁵ Among its key psychological benefits, breastfeeding is associated with an increase in maternal self-efficacy and, in some research, has been shown to be associated with a decreased risk of postpartum depression and stress.Additionally, breastfed infants experience lower rates of childhood infection and obesity, and improved nutrition, cognitive development, and immune function.⁶ The American Academy of Pediatrics recognizes these benefits and recommends that women exclusively breastfeed for 6 months postpartum and continue to breastfeed for 2 years or beyond if mutually desired by the mother and child.⁷ Absolute contraindications to breastfeeding must be ruled out (eg, infant classic galactosemia; maternal use of illicit substances such as cocaine, opioids, or phencyclidine; maternal HIV infection, etc).

The risks of breastfeeding by patients who have SMI must also be considered. In severe situations, the infant can be exposed to a mother’s agitation secondary to psychosis.^8,9 The transmission of antipsychotic medication through breastmilk and associated adverse effects (eg, sedation, poor feeding, and extrapyramidal symptoms) are also potential risks and varies among different antipsychotic medications.^1,10 Therefore, when prescribing an antipsychotic for a patient with SMI who breastfeeds, it is crucial to consider the medication’s safety profile as well as other factors, such as the relative infant dose (the weight-adjusted [ie, mg/kg] percentage of the maternal dosage ingested by a fully breastfed infant) and the molecular characteristics of the medication.^10-12 Neonates should be routinely monitored for adverse effects, medication toxicity, and withdrawal symptoms, and care should be coordinated with the infant’s pediatrician. Certain antipsychotic medications, such as aripiprazole, may impact breastmilk production through the dopamine agonist’s interference of the prolactin reflex and anticholinergic properties.^11,13 For a patient with SMI, perhaps the most significant risk involves the time and resources needed for breastfeeding, which can interfere with sleep and psychiatric treatment and possibly further exacerbate psychiatric symptoms.^14-16 Additionally, breastfeeding difficulties or disruption can increase the risk of psychiatric symptoms and psychological distress.¹⁷ In Ms. C’s case, there was a delay in the baby latching as well as multiple medical and psychiatric factors that hindered the milk-ejection reflex to properly initiate; both of these factors rendered breastfeeding particularly difficult while Ms. C was on the inpatient psychiatry unit.¹⁷ In comparison, Ms. S was able to bond with her infant shortly after delivery, which facilitated the milk-ejection reflex and lactation.

Patients who wish to directly breastfeed but struggle to do so while tending to their acute psychiatric condition can benefit from expression of breastmilk that can be provided to the infant or discarded to facilitate breastfeeding in the future.¹⁸ While expression of breastmilk may not be as advantageous for infant health as direct breastfeeding due to the potential changes in breastmilk composition from collecting, storing, and heating, this option can be more protective than formula feeding and facilitate future breastfeeding.¹⁹ In these clinical scenarios, it is standard care to provide a hospital-grade breast pump to the patient, much like a continuous positive airway pressure machine is provided to patients with obstructive sleep apnea.²⁰ However, there is often considerable difficulty obtaining proper breastfeeding equipment and a lack of services devoted to perinatal care in general inpatient settings. Barriers to direct breastfeeding and pumping of breastmilk are highlighted in the Table.²¹

Limitations on breastfeeding on an inpatient unit

The limitations in care and restrictions placed on breastfeeding are more optimally addressed in a mother and baby unit (MBU). MBUs are specialized inpatient psychiatric units designed for mothers experiencing severe perinatal psychiatric difficulties. Unlike general psychiatric units, MBUs allow for joint, full-time admission of mothers and their infants. These units also include multidisciplinary staff who specialize in treating perinatal mental health issues as well as infant care and child development.²² Admission into an MBU is considered best practice for new mothers requiring treatment, particularly in the United Kingdom, Australia, and France, as it is well-recognized that the separation of mother and baby can be psychologically harmful.²³ In the UK, most patients admitted to an MBU showed significant improvement of their psychiatric symptoms and reported overall high satisfaction with care.^24,25 Patients who experience postpartum psychosis prefer MBUs over general psychiatric units because the latter often lack specialized perinatal support, appropriate visitor arrangements, and adequate time with their infant.^26-28

Continue to: The resistance to adopting MBUs in the United States...

The resistance to adopting MBUs in the United States has posed significant barriers in care for perinatal patients and has been attributed to financial barriers, medicolegal risk, staffing, and safety concerns.²⁹ Though currently there are no MBUs in the US, other specialized units have been created. A partial day hospitalization program created in 2000 in Rhode Island for mothers and infants revolutionized the psychiatric care experience for new mothers.³⁰ Since then, other institutions have significantly expanded their services to include perinatal psychiatry inpatient units, yet unlike MBUs, these units typically do not provide overnight rooming-in with infants.³¹ They have the necessary resources and facilities to accommodate the mother’s needs and maximize positive mother-infant interaction, while actively integrating the infant into the mother’s treatment. Breast pumping is treated as a necessary medical procedure and patients can easily access hospital-grade breast pumps with staff supervision. At one such perinatal psychiatric inpatient unit, high rates of treatment satisfaction and significant improvements in symptoms of depression, anxiety, active suicidal ideation, and overall functioning were observed at discharge.³² Therefore, it is crucial to incorporate strategies in general psychiatry units to improve perinatal care, acknowledging that most patients will not have access to these specialized units.²¹

A framework to approaching the relational ethics decisions

An interdisciplinary team used a relational ethics perspective to carefully analyze the risks and benefits of these complex cases. In Figure 1, we propose a framework for the relational ethics decisions of breastfeeding on general inpatient psychiatric units. In creating this framework, we considered principles of autonomy, beneficence, and nonmaleficence, along with the medical and logistical barriers to breastfeeding.

In Ms. C’s case, the team determined that the risks—which included disrupting the mother’s psychiatric treatment, exposing her to psychological harm due to increasing attachment before remanding the child to CPS custody, and risks to the child due to potential unpredictable agitation driven by the treatment-refractory psychosis of the mother as well as that of other psychiatric patients—outweighed the benefits of breastfeeding. We instead recommended breast pumping as an alternative once Ms. C’s psychiatric stability improved. We presented Ms. C with the option of breast pumping on postpartum Day 5. During a 1-day period in which she showed improved behavioral control, she was counseled on the risks and benefits of breastfeeding and exclusive pumping and was notified that the team would help her with the necessary resources, including consultation with a lactation specialist and breast pump. Despite lactation consultant support, Ms. C had low milk production and difficulty with hand expression, which was very discouraging to her. She produced 1 ounce of milk that was shared with the newborn while in the NICU. Because Ms. C’s psychiatric symptoms continued to be severe, with lability and aggression, and because pumping was triggering distress, the multidisciplinary team determined the best course of care would be to focus on her psychiatric recovery rather than on pumping breastmilk. To reduce milk production and minimize discomfort secondary to breast engorgement, the lactation consultant recommended cold compresses, pain management, and compression of breasts. Ultimately, the mother-infant dyad was unable to reap the benefits of breastfeeding (via pumping or direct breastfeeding) due to the mother’s underlying psychiatric illness, although the staffing, psychosocial support, and logistical limitations contributed to this outcome.³³

In Ms. S’s case, the treatment team determined that there were no medical or psychiatric contraindications to breastfeeding, and she was counseled on the risks and benefits of direct breastfeeding and pumping. The treatment team determined it was safe for Ms. S to directly breastfeed as there were no concerns for infant harm post­delivery with constant supervision while on the obstetrics floor. The patient opted to directly breastfeed, which was successful with the guidance of a lactation specialist. When she was transferred to the psychiatric unit on postpartum Day 2, her child was discharged home with the husband. The patient was then encouraged to pump while the psychiatrists monitored her symptoms closely and facilitated increased staff and resources. Transportation of breastmilk was made possible by the family, and on postpartum Day 5, as the patient maintained psychiatric stability, the team discussed with Ms. S and her husband the prospect of direct breastfeeding. The treatment team arranged for separate visitation hours to minimize the possibility of exposing the infant to aggression from other patients on the unit and advocated with hospital leadership to approve of infant visitation on the unit.

Impact of involvement of Child Protective Services

The involvement of CPS also added complexity to Ms. C’s case. Without proper legal guidance, mothers with psychosis who lose custody can find it difficult to navigate the legal system and maintain contact with their children.³⁴ As the prevalence of custody loss in mothers with psychosis is high (approximately 50% according to research published in the last 10 years), effective interventions to reunite the mother and child must be promoted (Figure 2).^35-39 Ultimately, the goal of psychiatric hospitalization for perinatal women who have SMI is psychiatric stabilization. The preemptive involvement of psychiatry is crucial because it can allow for early postpartum planning and can provide an opportunity to address feeding options and custody concerns with the patient, social supports and services, and various medical teams. In Ms. C’s case, she visited her baby in the NICU on postpartum Day 2 without consultation with psychiatry or CPS, which posed risks to the patient, infant, and staff. It is vital that various clinicians collaborate with each other and the patient, working towards the goal of optimizing the patient’s mental health to allow for parenting rights in the future and maximizing a sustainable attachment between the parent and child. In Ms. S’s case, the husband was able to facilitate caring for the baby while the mother was hospitalized and played an integral role in the feeding process via pumped breastmilk and transport of the infant for direct breastfeeding.

Continue to: The differences in these 2 cases...

The differences in these 2 cases show the extreme importance of social support to benefit both the mother and child, and the need for more comprehensive social services for women who do not have a social safety net.

Bottom Line

These complex cases highlight an ethical decision-making approach to breastfeeding in perinatal women who have serious mental illness. Collaborative care and shared decision-making, which highlight the interests of the mother and baby, are crucial when assessing the risks and benefits of breastfeeding and pumping breastmilk. Our relational ethics framework can be used to better evaluate and implement breastfeeding options on general psychiatric units.

Related Resources

• Tillman B, Sloan N, Westmoreland P. How COVID-19 affects peripartum women’s mental health. Current Psychiatry. 2021;20(6):18-22. doi:10.12788/cp.0129
• Koch J, Preinitz J. Antidepressants for patients who are breastfeeding: what to consider. Current Psychiatry. 2023;22(5):20-23,48. doi:10.12788/cp.0355

Drug Brand Names

Aripiprazole • Abilify
Olanzapine • Zyprexa
Risperidone • Risperdal

Our psychiatric research, which found a high incidence of undiagnosed mental illness in mass shooters, was recently awarded the esteemed Psychodynamic Psychiatry Journal Prize for best paper published in the last 2 years (2022-2023). The editors noted our integrity in using quantitative data to argue against the common, careless assumption that mass shooters are not mentally ill.

Some of the mass shooters we studied were motivated by religious or political ideologies that were considered forms of terrorism. Given the current tragically violent landscape both at home and in Israel/Palestine, the “desire for destruction” is vital to understand.

Although there have been a limited number of psychiatric studies of perpetrators of mass shootings, our team took the first step to lay the groundwork by conducting a systematic, quantitative study. Our psychiatric research team’s research findings were published in the Journal of Clinical Psychopharmacology and then in greater detail in Psychodynamic Psychiatry,^1,2 which provided important context to the complicated backgrounds of these mass shooters who suffer from abuse, marginalization, and severe undiagnosed brain illness.³

Dr. Cerfolio

The Mother Jones database of 115 mass shootings from 1982 to 2019 was used to study retrospectively 55 shooters in the United States. We developed a uniform, comprehensive, 62-item questionnaire to compile the data collection from multiple sources and record our psychiatric assessments of the assailants, using DSM-5 criteria. After developing this detailed psychiatric assessment questionnaire, psychiatric researchers evaluated the weight and quality of clinical evidence by (1) interviewing forensic psychiatrists who had assessed the assailant following the crime, and/or (2) reviewing court records of psychiatric evaluations conducted during the postcrime judicial proceedings to determine the prevalence of psychiatric illness. Rather than accepting diagnoses from forensic psychiatrists and/or court records, our team independently reviewed the clinical data gathered from multiple sources to apply the DSM-5 criteria to diagnose mental illness.

In most incidents in the database, the perpetrator died either during or shortly after the crime. We examined every case (n=35) in which the assailant survived, and criminal proceedings were instituted.

Of the 35 cases in which the assailant survived and criminal proceedings were instituted, there was insufficient information to make a diagnosis in 3 cases. Of the remaining 32 cases in which we had sufficient information, we determined that 87.5% had the following psychiatric diagnosis: 18 assailants (56%) had schizophrenia, while 10 assailants (31%) had other psychiatric diagnoses: 3 had bipolar I disorder, 2 had delusional disorders (persecutory), 2 had personality disorders (1 paranoid, 1 borderline), 2 had substance-related disorders without other psychiatric diagnosis, and 1 had post-traumatic stress disorder (PTSD).

Out of the 32 surviving assailants for whom we have sufficient evidence, 87.5% of perpetrators of mass shootings were diagnosed with major psychiatric illness, and none were treated appropriately with medication at the time of the crime. Four assailants (12.5%) had no psychiatric diagnosis that we could discern. Of the 18 surviving assailants with schizophrenia, no assailant was on antipsychotic medication for the treatment of schizophrenia prior to the crime. Of the 10 surviving assailants with other psychiatric illnesses, no assailant was on antipsychotic and/or appropriate medication.

In addition, we found that the clinical misdiagnosis of early-onset schizophrenia was associated with the worsening of many of these assailants’ psychotic symptoms. Many of our adolescent shooters prior to the massacre had been misdiagnosed with attention-deficit disorder (ADD), major depression disorder (MDD), or autism spectrum disorder.

Though the vast majority of those suffering from psychiatric illnesses who are appropriately treated are not violent, there is a growing body of scientific research that indicates a strong association of untreated brain illness with those who commit mass shootings.^4,5,6 This research demonstrates that such untreated illness combined with access to firearms poses a lethal threat to society.

Stanford University

Most of the assailants also experienced profound estrangement, not only from families and friends, but most importantly from themselves. Being marginalized rendered them more vulnerable to their untreated psychiatric illness and to radicalization online, which fostered their violence. While there are complex reasons that a person is not diagnosed, there remains a vital need to decrease the stigma of mental illness to enable those with psychiatric illness to be more respected, less marginalized, and encouraged to receive effective psychiatric treatments.

Dr. Cerfolio is author of “Psychoanalytic and Spiritual Perspectives on Terrorism: Desire for Destruction.” She is clinical assistant professor at the Icahn School of Medicine at Mount Sinai, New York. Dr. Glick is Professor Emeritus, Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, Stanford, Calif.

References

1. Glick ID, et al. Domestic Mass Shooters: The Association With Unmedicated and Untreated Psychiatric Illness. J Clin Psychopharmacol. 2021 Jul-Aug;41(4):366-369. doi: 10.1097/JCP.0000000000001417.

2. Cerfolio NE, et al. A Retrospective Observational Study of Psychosocial Determinants and Psychiatric Diagnoses of Mass Shooters in the United States. Psychodyn Psychiatry. 2022 Fall;50(3):1-16. doi: 10.1521/pdps.2022.50.5.001.

3. Cerfolio NE. The Parkland gunman, a horrific crime, and mental illness. The New York Times. 2022 Oct 14. www.nytimes.com/2022/10/14/opinion/letters/jan-6-panel-trump.html#link-5e2ccc1.

4. Corner E, et al. Mental Health Disorders and the Terrorist: A Research Note Probing Selection Effects and Disorder Prevalence. Stud Confl Terror. 2016 Jan;39(6):560–568. doi: 10.1080/1057610X.2015.1120099.

5. Gruenewald J, et al. Distinguishing “Loner” Attacks from Other Domestic Extremist Violence. Criminol Public Policy. 2013 Feb;12(1):65–91. doi: 10.1111/1745-9133.12008.

6. Lankford A. Detecting mental health problems and suicidal motives among terrorists and mass shooters. Crim Behav Ment Health. 2016 Dec;26(5):315-321. doi: 10.1002/cbm.2020.

Our psychiatric research, which found a high incidence of undiagnosed mental illness in mass shooters, was recently awarded the esteemed Psychodynamic Psychiatry Journal Prize for best paper published in the last 2 years (2022-2023). The editors noted our integrity in using quantitative data to argue against the common, careless assumption that mass shooters are not mentally ill.

Some of the mass shooters we studied were motivated by religious or political ideologies that were considered forms of terrorism. Given the current tragically violent landscape both at home and in Israel/Palestine, the “desire for destruction” is vital to understand.

Although there have been a limited number of psychiatric studies of perpetrators of mass shootings, our team took the first step to lay the groundwork by conducting a systematic, quantitative study. Our psychiatric research team’s research findings were published in the Journal of Clinical Psychopharmacology and then in greater detail in Psychodynamic Psychiatry,^1,2 which provided important context to the complicated backgrounds of these mass shooters who suffer from abuse, marginalization, and severe undiagnosed brain illness.³

Dr. Cerfolio

The Mother Jones database of 115 mass shootings from 1982 to 2019 was used to study retrospectively 55 shooters in the United States. We developed a uniform, comprehensive, 62-item questionnaire to compile the data collection from multiple sources and record our psychiatric assessments of the assailants, using DSM-5 criteria. After developing this detailed psychiatric assessment questionnaire, psychiatric researchers evaluated the weight and quality of clinical evidence by (1) interviewing forensic psychiatrists who had assessed the assailant following the crime, and/or (2) reviewing court records of psychiatric evaluations conducted during the postcrime judicial proceedings to determine the prevalence of psychiatric illness. Rather than accepting diagnoses from forensic psychiatrists and/or court records, our team independently reviewed the clinical data gathered from multiple sources to apply the DSM-5 criteria to diagnose mental illness.

In most incidents in the database, the perpetrator died either during or shortly after the crime. We examined every case (n=35) in which the assailant survived, and criminal proceedings were instituted.

Of the 35 cases in which the assailant survived and criminal proceedings were instituted, there was insufficient information to make a diagnosis in 3 cases. Of the remaining 32 cases in which we had sufficient information, we determined that 87.5% had the following psychiatric diagnosis: 18 assailants (56%) had schizophrenia, while 10 assailants (31%) had other psychiatric diagnoses: 3 had bipolar I disorder, 2 had delusional disorders (persecutory), 2 had personality disorders (1 paranoid, 1 borderline), 2 had substance-related disorders without other psychiatric diagnosis, and 1 had post-traumatic stress disorder (PTSD).

Out of the 32 surviving assailants for whom we have sufficient evidence, 87.5% of perpetrators of mass shootings were diagnosed with major psychiatric illness, and none were treated appropriately with medication at the time of the crime. Four assailants (12.5%) had no psychiatric diagnosis that we could discern. Of the 18 surviving assailants with schizophrenia, no assailant was on antipsychotic medication for the treatment of schizophrenia prior to the crime. Of the 10 surviving assailants with other psychiatric illnesses, no assailant was on antipsychotic and/or appropriate medication.

In addition, we found that the clinical misdiagnosis of early-onset schizophrenia was associated with the worsening of many of these assailants’ psychotic symptoms. Many of our adolescent shooters prior to the massacre had been misdiagnosed with attention-deficit disorder (ADD), major depression disorder (MDD), or autism spectrum disorder.

Though the vast majority of those suffering from psychiatric illnesses who are appropriately treated are not violent, there is a growing body of scientific research that indicates a strong association of untreated brain illness with those who commit mass shootings.^4,5,6 This research demonstrates that such untreated illness combined with access to firearms poses a lethal threat to society.

Stanford University

Most of the assailants also experienced profound estrangement, not only from families and friends, but most importantly from themselves. Being marginalized rendered them more vulnerable to their untreated psychiatric illness and to radicalization online, which fostered their violence. While there are complex reasons that a person is not diagnosed, there remains a vital need to decrease the stigma of mental illness to enable those with psychiatric illness to be more respected, less marginalized, and encouraged to receive effective psychiatric treatments.

Dr. Cerfolio is author of “Psychoanalytic and Spiritual Perspectives on Terrorism: Desire for Destruction.” She is clinical assistant professor at the Icahn School of Medicine at Mount Sinai, New York. Dr. Glick is Professor Emeritus, Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, Stanford, Calif.

References

1. Glick ID, et al. Domestic Mass Shooters: The Association With Unmedicated and Untreated Psychiatric Illness. J Clin Psychopharmacol. 2021 Jul-Aug;41(4):366-369. doi: 10.1097/JCP.0000000000001417.

2. Cerfolio NE, et al. A Retrospective Observational Study of Psychosocial Determinants and Psychiatric Diagnoses of Mass Shooters in the United States. Psychodyn Psychiatry. 2022 Fall;50(3):1-16. doi: 10.1521/pdps.2022.50.5.001.

3. Cerfolio NE. The Parkland gunman, a horrific crime, and mental illness. The New York Times. 2022 Oct 14. www.nytimes.com/2022/10/14/opinion/letters/jan-6-panel-trump.html#link-5e2ccc1.

4. Corner E, et al. Mental Health Disorders and the Terrorist: A Research Note Probing Selection Effects and Disorder Prevalence. Stud Confl Terror. 2016 Jan;39(6):560–568. doi: 10.1080/1057610X.2015.1120099.

5. Gruenewald J, et al. Distinguishing “Loner” Attacks from Other Domestic Extremist Violence. Criminol Public Policy. 2013 Feb;12(1):65–91. doi: 10.1111/1745-9133.12008.

6. Lankford A. Detecting mental health problems and suicidal motives among terrorists and mass shooters. Crim Behav Ment Health. 2016 Dec;26(5):315-321. doi: 10.1002/cbm.2020.

Our psychiatric research, which found a high incidence of undiagnosed mental illness in mass shooters, was recently awarded the esteemed Psychodynamic Psychiatry Journal Prize for best paper published in the last 2 years (2022-2023). The editors noted our integrity in using quantitative data to argue against the common, careless assumption that mass shooters are not mentally ill.

Some of the mass shooters we studied were motivated by religious or political ideologies that were considered forms of terrorism. Given the current tragically violent landscape both at home and in Israel/Palestine, the “desire for destruction” is vital to understand.

Although there have been a limited number of psychiatric studies of perpetrators of mass shootings, our team took the first step to lay the groundwork by conducting a systematic, quantitative study. Our psychiatric research team’s research findings were published in the Journal of Clinical Psychopharmacology and then in greater detail in Psychodynamic Psychiatry,^1,2 which provided important context to the complicated backgrounds of these mass shooters who suffer from abuse, marginalization, and severe undiagnosed brain illness.³

Dr. Cerfolio

The Mother Jones database of 115 mass shootings from 1982 to 2019 was used to study retrospectively 55 shooters in the United States. We developed a uniform, comprehensive, 62-item questionnaire to compile the data collection from multiple sources and record our psychiatric assessments of the assailants, using DSM-5 criteria. After developing this detailed psychiatric assessment questionnaire, psychiatric researchers evaluated the weight and quality of clinical evidence by (1) interviewing forensic psychiatrists who had assessed the assailant following the crime, and/or (2) reviewing court records of psychiatric evaluations conducted during the postcrime judicial proceedings to determine the prevalence of psychiatric illness. Rather than accepting diagnoses from forensic psychiatrists and/or court records, our team independently reviewed the clinical data gathered from multiple sources to apply the DSM-5 criteria to diagnose mental illness.

In most incidents in the database, the perpetrator died either during or shortly after the crime. We examined every case (n=35) in which the assailant survived, and criminal proceedings were instituted.

Of the 35 cases in which the assailant survived and criminal proceedings were instituted, there was insufficient information to make a diagnosis in 3 cases. Of the remaining 32 cases in which we had sufficient information, we determined that 87.5% had the following psychiatric diagnosis: 18 assailants (56%) had schizophrenia, while 10 assailants (31%) had other psychiatric diagnoses: 3 had bipolar I disorder, 2 had delusional disorders (persecutory), 2 had personality disorders (1 paranoid, 1 borderline), 2 had substance-related disorders without other psychiatric diagnosis, and 1 had post-traumatic stress disorder (PTSD).

Out of the 32 surviving assailants for whom we have sufficient evidence, 87.5% of perpetrators of mass shootings were diagnosed with major psychiatric illness, and none were treated appropriately with medication at the time of the crime. Four assailants (12.5%) had no psychiatric diagnosis that we could discern. Of the 18 surviving assailants with schizophrenia, no assailant was on antipsychotic medication for the treatment of schizophrenia prior to the crime. Of the 10 surviving assailants with other psychiatric illnesses, no assailant was on antipsychotic and/or appropriate medication.

In addition, we found that the clinical misdiagnosis of early-onset schizophrenia was associated with the worsening of many of these assailants’ psychotic symptoms. Many of our adolescent shooters prior to the massacre had been misdiagnosed with attention-deficit disorder (ADD), major depression disorder (MDD), or autism spectrum disorder.

Though the vast majority of those suffering from psychiatric illnesses who are appropriately treated are not violent, there is a growing body of scientific research that indicates a strong association of untreated brain illness with those who commit mass shootings.^4,5,6 This research demonstrates that such untreated illness combined with access to firearms poses a lethal threat to society.

Stanford University

Most of the assailants also experienced profound estrangement, not only from families and friends, but most importantly from themselves. Being marginalized rendered them more vulnerable to their untreated psychiatric illness and to radicalization online, which fostered their violence. While there are complex reasons that a person is not diagnosed, there remains a vital need to decrease the stigma of mental illness to enable those with psychiatric illness to be more respected, less marginalized, and encouraged to receive effective psychiatric treatments.

Dr. Cerfolio is author of “Psychoanalytic and Spiritual Perspectives on Terrorism: Desire for Destruction.” She is clinical assistant professor at the Icahn School of Medicine at Mount Sinai, New York. Dr. Glick is Professor Emeritus, Department of Psychiatry and Behavioral Sciences at Stanford University School of Medicine, Stanford, Calif.

References

1. Glick ID, et al. Domestic Mass Shooters: The Association With Unmedicated and Untreated Psychiatric Illness. J Clin Psychopharmacol. 2021 Jul-Aug;41(4):366-369. doi: 10.1097/JCP.0000000000001417.

2. Cerfolio NE, et al. A Retrospective Observational Study of Psychosocial Determinants and Psychiatric Diagnoses of Mass Shooters in the United States. Psychodyn Psychiatry. 2022 Fall;50(3):1-16. doi: 10.1521/pdps.2022.50.5.001.

3. Cerfolio NE. The Parkland gunman, a horrific crime, and mental illness. The New York Times. 2022 Oct 14. www.nytimes.com/2022/10/14/opinion/letters/jan-6-panel-trump.html#link-5e2ccc1.

4. Corner E, et al. Mental Health Disorders and the Terrorist: A Research Note Probing Selection Effects and Disorder Prevalence. Stud Confl Terror. 2016 Jan;39(6):560–568. doi: 10.1080/1057610X.2015.1120099.

5. Gruenewald J, et al. Distinguishing “Loner” Attacks from Other Domestic Extremist Violence. Criminol Public Policy. 2013 Feb;12(1):65–91. doi: 10.1111/1745-9133.12008.

6. Lankford A. Detecting mental health problems and suicidal motives among terrorists and mass shooters. Crim Behav Ment Health. 2016 Dec;26(5):315-321. doi: 10.1002/cbm.2020.

Delirious mania is a syndrome characterized by the acute onset of severe hyperactivity, psychosis, catatonia, and intermittent confusion. While there have been growing reports of this phenomenon over the last 2 decades, it remains poorly recognized and understood.^1,2 There is no widely accepted nosology for delirious mania and the condition is absent from DSM-5, which magnifies the difficulties in making a timely diagnosis and initiating appropriate treatment. Delayed diagnosis and treatment may result in a detrimental outcome.^2,3 Delirious mania has also been labeled as lethal catatonia, specific febrile delirium, hyperactive or exhaustive mania, and Bell’s mania.^2,4,5 The characterization and diagnosis of this condition have a long and inconsistent history (Box^1,6-11).

Box

Delirious mania continues to be met with incertitude in clinical practice, and numerous inconsistencies have been reported in the literature. For example, some cases that have been reported as delirious mania had more evidence of primary delirium due to another medical condition or primary mania.^12,13 Other cases have demonstrated swift improvement of symptoms after monotherapy with antipsychotics without a trial of benzodiazepines or electroconvulsive therapy (ECT); the exclusion of a sudden onset questions the validity of the diagnosis and promotes the use of less efficacious treatments.^14,15 Other reports have confirmed that the diagnosis is missed when certain symptoms are more predominant, such as a thought disorder (acute schizophrenia), grandiosity and delusional ideation (bipolar disorder [BD]), and less commonly assessed catatonic signs (ambitendency, automatic obedience). These symptoms are mistakenly attributed to the respective disease.^1,16 This especially holds true when delirious mania is initially diagnosed as a primary psychosis, which leads to the administration of antipsychotics.¹⁷ Other cases have reported that delirious mania was resistant to treatment, but ECT was never pursued.¹⁸

In this review, we provide a more comprehensive perspective of the clinical presentation, pathogenesis, and management of delirious mania. We searched PubMed and Google Scholar using the keywords “delirious mania,” “delirious mania AND catatonia,” or “manic delirium.” Most articles we found were case reports, case series, or retrospective chart reviews. There were no systematic reviews, meta analyses, or randomized control trials (RCTs). The 12 articles included in this review consist of 7 individual case reports, 4 case series, and 1 retrospective chart review that describe a total of 36 cases (Table^{1,2,5,17,19-26}).

Clinical presentation: What to look for

Patients with delirious mania typically develop symptoms extremely rapidly. In virtually all published literature, symptoms were reported to emerge within hours to days and consisted of severe forms of mania, psychosis, and delirium; 100% of the cases in our review had these symptoms. Commonly reported symptoms were:

• intense excitement
• emotional lability
• grandiose delusions
• profound insomnia
• pressured and rapid speech
• auditory and visual hallucinations
• hypersexuality
• thought disorganization.

Exquisite paranoia can also result in violent aggression (and may require the use of physical restraints). Patients may confine themselves to very small spaces (such as a closet) in response to the intense paranoia. Impairments in various neurocognitive domains—including inability to focus; disorientation; language and visuospatial disturbances; difficulty with shifting and sustaining attention; and short-term memory impairments—have been reported. Patients often cannot recall the events during the episode.^1,2,5,27,28

Catatonia has been closely associated with delirious mania.²⁹ Features of excited catatonia—such as excessive motor activity, negativism, grimacing, posturing, echolalia, echopraxia, stereotypy, automatic obedience, verbigeration, combativeness, impulsivity, and rigidity—typically accompany delirious mania.^1,5,10,19,27

In addition to these symptoms, patients may engage in specific behaviors. They may exhibit inappropriate toileting such as smearing feces on walls or in bags, fecal or urinary incontinence, disrobing or running naked in public places, or pouring liquid on the floor or on one’s head.^1,2

Continue to: Of the 36 cases...

Of the 36 cases reported in the literature we reviewed, 20 (55%) were female. Most patients had an underlining psychiatric condition, including BD (72%), major depressive disorder (8%), and schizophrenia (2%). Three patients had no psychiatric history.

Physical examination

On initial presentation, a patient with delirious mania may be dehydrated, with dry mucous membranes, pale conjunctiva, tongue dryness, and poor skin turgor.^28,30 Due to excessive motor activity, diaphoresis with tachycardia, fluctuating blood pressure, and fever may be present.³¹

Certain basic cognitive tasks should be assessed to determine the patient’s orientation to place, date, and time. Assess if the patient can recall recent events, names of objects, or perform serial 7s; clock drawing capabilities also should be ascertained.^1,2,5 A Mini-Mental State Examination is useful.³²

The Bush-Francis Catatonia Rating Scale should be used to elicit features of catatonia, such as waxy flexibility, negativism, gegenhalten, mitgehen, catalepsy, ambitendency, automatic obedience, and grasp reflex.¹⁰

Laboratory findings are nonspecific

Although no specific laboratory findings are associated with delirious mania, bloodwork and imaging are routinely investigated, especially if delirium characteristics are most striking. A complete blood count, chemistries, hepatic panel, thyroid functioning, blood and/or urine cultures, creatinine phosphokinase (CPK), and urinalysis can be ordered. Head imaging such as MRI and CT to rule out intracranial pathology are typically performed.¹⁹ However, the diagnosis of delirious mania is based on the presence of the phenotypic features, by verification of catatonia, and by the responsiveness to the treatment delivered.²⁹

Continue to: Pathogenisis: Several hypotheses

The pathogenesis of delirious mania is not well understood. There are several postulations but no salient theory. Most patients with delirious mania have an underlying systemic medical or psychiatric condition.

Mood disorders. Patients with BD or schizoaffective disorder are especially susceptible to delirious mania. The percentage of manic patients who present with delirious mania varies by study. One study suggested approximately 19% have features of the phenomenon,³³ while others estimated 15% to 25%.³⁴ Elias et al³⁵ calculated that 15% of patients with mania succumb to manic exhaustion; from this it can be reasonably concluded that these were cases of misdiagnosed delirious mania.

Delirium hypothesis. Patients with delirious mania typically have features of delirium, including fluctuation of consciousness, disorientation, and/or poor sleep-wake cycle.³⁶ During rapid eye movement (REM) and non-REM sleep, memory circuits are fortified. When there is a substantial loss of REM and non-REM sleep, these circuits become faulty, even after 1 night. Pathological brain waves on EEG reflect the inability to reinforce the memory circuits. Patients with these waves may develop hallucinations, bizarre delusions, and altered sensorium. ECT reduces the pathological slow wave morphologies, thus restoring the synaptic maintenance and correcting the incompetent circuitry. This can explain the robust and rapid response of ECT in a patient with delirious mania.^37,38

Neurotransmitter hypothesis. It has been shown that in patients with delirious mania there is dysregulation of dopamine transport, which leads to dopamine overflow in the synapse. In contrast to a drug effect (ie, cocaine or methamphetamine) that acts by inhibiting dopamine reuptake, dopamine overflow in delirious mania is caused by the loss of dopamine transporter regulation. This results in a dysfunctional dopaminergic state that precipitates an acute state of delirium and agitation.^39,40

Serotonin plays a role in mood disorders, including mania and depression.^41,42 More specifically, serotonin has been implicated in impulsivity and aggression as shown by reduced levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) and depletion of 5-hydroxytryptophan (5-HTP).⁴³

Continue to: Alterations in gamma-aminobutyric acid (GABA) transmission...

Alterations in gamma-aminobutyric acid (GABA) transmission are known to occur in delirium and catatonia. In delirium, GABA signaling is increased, which disrupts the circadian rhythm and melatonin release, thus impairing the sleep-wake cycle.⁴⁴ Deficiencies in acetylcholine and melatonin are seen as well as excess of other neurotransmitters, including norepinephrine and glutamate.⁴⁵ Conversely, in catatonia, functional imaging studies found decreased GABA-A binding in orbito­frontal, prefrontal, parietal, and motor cortical regions.⁴⁶ A study analyzing 10 catatonic patients found decreased density of GABA-A receptors in the left sensorimotor cortex compared to psychiatric and healthy controls.⁴⁷

Other neurotransmitters, such as glutamate, at the N-methyl-D-aspartate receptors (NMDAR) have been hypothesized to be hyperactive, causing downstream dysregulation of GABA functioning.⁴⁸ However, the exact connection between delirious mania and all these receptors and neurotransmitters remains unknown.

Encephalitis hypothesis. The relationship between delirious mania and autoimmune encephalitis suggests delirious mania has etiologies other than a primary psychiatric illness. In a 2020 retrospective study⁴⁹ that analyzed 79 patients with anti-NMDAR encephalitis, 25.3% met criteria for delirious mania, and 95% of these patients had catatonic features. Dalmau et al⁵⁰ found that in many cases, patients tend to respond to ECT; in a cases series of 3 patients, 2 responded to benzodiazepines.

COVID-19 hypothesis. The SARS-CoV-2 virion has been associated with many neuropsychiatric complications, including mood, psychotic, and neurocognitive disorders.^51,52 There also have been cases of COVID-19–induced catatonia.^53-55 One case of delirious mania in a patient with COVID-19 has been reported.²¹ The general mechanism has been proposed to be related to the stimulation of the proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, which the virus produces in large quantities.⁵⁶ These cytokines have been linked to psychosis and other psychiatric disorders.⁵⁷ The patient with COVID-19–induced delirious mania had elevated inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, ferritin, and D-dimer, which supports a proinflammatory state. This patient had a complete resolution of symptoms with ECT.²¹

Management: Benzodiazepines and ECT

A step-by-step algorithm for managing delirious mania is outlined in the Figure. Regardless of the underlining etiology, management of delirious mania consists of benzodiazepines (lorazepam and diazepam); prompt use of ECT, particularly for patients who do not improve with large doses of lorazepam; or (if applicable) continued treatment of the underlining medical condition, which does not preclude the use of benzodiazepines or ECT. Recent reports^27,58 have described details for using ECT for delirious mania, highlighting the use of high-energy dosing, bilateral electrode placement, and frequent sessions.

Continue to: Knowing which medications...

Knowing which medications to avoid is as important as knowing which agents to administer. Be vigilant in avoiding high-potency antipsychotics, as these medications can worsen extrapyramidal symptoms and may precipitate seizures or neuroleptic malignant syndrome (NMS).²⁸ Anticholinergic agents should also be avoided because they worsen confusion. Although lithium is effective in BD, in delirious mania, high doses of lithium and haloperidol may cause severe encephalopathic syndromes, with symptoms that can include lethargy, tremors, cerebellar dysfunction, and worsened confusion; it may also cause widespread and irreversible brain damage.⁵⁹While positive outcomes have been documented when using a combination of antipsychotics and lithium,^8,60 this approach should be considered carefully and tailored to individual cases, taking into account the severity of manic and psychotic symptoms in addition to the level of catatonia.

Due to long periods of hyperactivity, withdrawal, and diaphoresis, patients with delirious mania may be severely dehydrated with metabolic derangements, including elevated CPK due to rhabdomyolysis from prolonged exertion, IM antipsychotics, or rigidity. To prevent acute renal failure, this must be immediately addressed with rapid fluid resuscitation and electrolyte repletion.⁶¹

Benzodiazepines. The rapid use of lorazepam should be initiated when delirious mania is suspected. Doses of 6 to 20 mg have been reported to be effective if tolerated.^5,20 Typically, high-dose lorazepam will not have the sedative effect that would normally occur in a patient who does not have delirious mania.² Lorazepam should be titrated until full resolution of symptoms. Doses up to 30 mg have been reported as effective and tolerable.⁶² In our literature review, 50% of patients (18/36) responded or partially responded to lorazepam. However, only 3 case reports documented a complete remission with lorazepam, and many patients needed ECT for remission of symptoms.

ECT is generally reserved for patients who are not helped by benzodiazepine therapy, which is estimated to be up to 20%.⁵ ECT is highly effective in delirious mania, with remission rates ranging from 80% to 100%.¹ ECT is also effective in acute non­delirious mania (comparable to depression); however, it is only used in a small minority of cases (0.2% to 12%).³⁵ In our review, 58% of cases (21/36) reported using ECT, and in all cases it resulted in complete remission.

A dramatic improvement can be seen even after a single ECT session, though most patients show improvement after 4 sessions or 3 to 7 days.^1,2,5 In our review, most patients received 4 to 12 sessions until achieving complete remission.

Continue to: No RCTs have evaluated...

No RCTs have evaluated ECT electrode placement in patients with delirious mania. However, several RCTs have investigated electrode placement in patients with acute nondelirious mania. Hiremani et al⁶³ found that bitemporal placement had a more rapid response rate than bifrontal placement, but there was no overall difference in response rate. Barekatain et al⁶⁴ found no difference between these 2 bilateral approaches. Many of the delirious mania cases report using a bilateral placement (including 42% of the ECT cases in our review) due to the emergent need for rapid relief of symptoms, which is especially necessary if the patient is experiencing hemodynamic instability, excessive violence, risk for self-harm, worsening delirium, or resistance to lorazepam.

Prognosis: Often fatal if left untreated

Patients with delirious mania are at high risk to progress to a more severe form of NMS or malignant catatonia. Therefore, high-potency antipsychotics should be avoided; mortality can be elevated from 60% without antipsychotics to 78% with antipsychotics.⁴ Some researchers estimate 75% to 78% of cases of delirious mania can be fatal if left untreated.^3,6

Bottom Line

Delirious mania is routinely mistaken for more conventional manic or psychotic disorders. Clinicians need to be able to rapidly recognize the symptoms of this syndrome, which include mania, psychosis, delirium, and possible catatonia, so they can avoid administering toxic agents and instead initiate effective treatments such as benzodiazepines and electroconvulsive therapy.

Related Resources

• Arsan C, Baker C, Wong J, et al. Delirious mania: an approach to diagnosis and treatment. Prim Care Companion CNS Disord. 2021;23(1):20f02744. doi:10.4088/PCC.20f02744
• Lamba G, Kennedy EA, Vu CP. Case report: ECT for delirious mania. Clinical Psychiatry News. December 14, 2021. https://www.mdedge.com/psychiatry/article/249909/bipolar-disorder/case-report-ect-delirious-mania

Drug Brand Names

Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan

Delirious mania is a syndrome characterized by the acute onset of severe hyperactivity, psychosis, catatonia, and intermittent confusion. While there have been growing reports of this phenomenon over the last 2 decades, it remains poorly recognized and understood.^1,2 There is no widely accepted nosology for delirious mania and the condition is absent from DSM-5, which magnifies the difficulties in making a timely diagnosis and initiating appropriate treatment. Delayed diagnosis and treatment may result in a detrimental outcome.^2,3 Delirious mania has also been labeled as lethal catatonia, specific febrile delirium, hyperactive or exhaustive mania, and Bell’s mania.^2,4,5 The characterization and diagnosis of this condition have a long and inconsistent history (Box^1,6-11).

Box

Delirious mania continues to be met with incertitude in clinical practice, and numerous inconsistencies have been reported in the literature. For example, some cases that have been reported as delirious mania had more evidence of primary delirium due to another medical condition or primary mania.^12,13 Other cases have demonstrated swift improvement of symptoms after monotherapy with antipsychotics without a trial of benzodiazepines or electroconvulsive therapy (ECT); the exclusion of a sudden onset questions the validity of the diagnosis and promotes the use of less efficacious treatments.^14,15 Other reports have confirmed that the diagnosis is missed when certain symptoms are more predominant, such as a thought disorder (acute schizophrenia), grandiosity and delusional ideation (bipolar disorder [BD]), and less commonly assessed catatonic signs (ambitendency, automatic obedience). These symptoms are mistakenly attributed to the respective disease.^1,16 This especially holds true when delirious mania is initially diagnosed as a primary psychosis, which leads to the administration of antipsychotics.¹⁷ Other cases have reported that delirious mania was resistant to treatment, but ECT was never pursued.¹⁸

In this review, we provide a more comprehensive perspective of the clinical presentation, pathogenesis, and management of delirious mania. We searched PubMed and Google Scholar using the keywords “delirious mania,” “delirious mania AND catatonia,” or “manic delirium.” Most articles we found were case reports, case series, or retrospective chart reviews. There were no systematic reviews, meta analyses, or randomized control trials (RCTs). The 12 articles included in this review consist of 7 individual case reports, 4 case series, and 1 retrospective chart review that describe a total of 36 cases (Table^{1,2,5,17,19-26}).

Clinical presentation: What to look for

Patients with delirious mania typically develop symptoms extremely rapidly. In virtually all published literature, symptoms were reported to emerge within hours to days and consisted of severe forms of mania, psychosis, and delirium; 100% of the cases in our review had these symptoms. Commonly reported symptoms were:

• intense excitement
• emotional lability
• grandiose delusions
• profound insomnia
• pressured and rapid speech
• auditory and visual hallucinations
• hypersexuality
• thought disorganization.

Exquisite paranoia can also result in violent aggression (and may require the use of physical restraints). Patients may confine themselves to very small spaces (such as a closet) in response to the intense paranoia. Impairments in various neurocognitive domains—including inability to focus; disorientation; language and visuospatial disturbances; difficulty with shifting and sustaining attention; and short-term memory impairments—have been reported. Patients often cannot recall the events during the episode.^1,2,5,27,28

Catatonia has been closely associated with delirious mania.²⁹ Features of excited catatonia—such as excessive motor activity, negativism, grimacing, posturing, echolalia, echopraxia, stereotypy, automatic obedience, verbigeration, combativeness, impulsivity, and rigidity—typically accompany delirious mania.^1,5,10,19,27

In addition to these symptoms, patients may engage in specific behaviors. They may exhibit inappropriate toileting such as smearing feces on walls or in bags, fecal or urinary incontinence, disrobing or running naked in public places, or pouring liquid on the floor or on one’s head.^1,2

Continue to: Of the 36 cases...

Of the 36 cases reported in the literature we reviewed, 20 (55%) were female. Most patients had an underlining psychiatric condition, including BD (72%), major depressive disorder (8%), and schizophrenia (2%). Three patients had no psychiatric history.

Physical examination

On initial presentation, a patient with delirious mania may be dehydrated, with dry mucous membranes, pale conjunctiva, tongue dryness, and poor skin turgor.^28,30 Due to excessive motor activity, diaphoresis with tachycardia, fluctuating blood pressure, and fever may be present.³¹

Certain basic cognitive tasks should be assessed to determine the patient’s orientation to place, date, and time. Assess if the patient can recall recent events, names of objects, or perform serial 7s; clock drawing capabilities also should be ascertained.^1,2,5 A Mini-Mental State Examination is useful.³²

The Bush-Francis Catatonia Rating Scale should be used to elicit features of catatonia, such as waxy flexibility, negativism, gegenhalten, mitgehen, catalepsy, ambitendency, automatic obedience, and grasp reflex.¹⁰

Laboratory findings are nonspecific

Although no specific laboratory findings are associated with delirious mania, bloodwork and imaging are routinely investigated, especially if delirium characteristics are most striking. A complete blood count, chemistries, hepatic panel, thyroid functioning, blood and/or urine cultures, creatinine phosphokinase (CPK), and urinalysis can be ordered. Head imaging such as MRI and CT to rule out intracranial pathology are typically performed.¹⁹ However, the diagnosis of delirious mania is based on the presence of the phenotypic features, by verification of catatonia, and by the responsiveness to the treatment delivered.²⁹

Continue to: Pathogenisis: Several hypotheses

The pathogenesis of delirious mania is not well understood. There are several postulations but no salient theory. Most patients with delirious mania have an underlying systemic medical or psychiatric condition.

Mood disorders. Patients with BD or schizoaffective disorder are especially susceptible to delirious mania. The percentage of manic patients who present with delirious mania varies by study. One study suggested approximately 19% have features of the phenomenon,³³ while others estimated 15% to 25%.³⁴ Elias et al³⁵ calculated that 15% of patients with mania succumb to manic exhaustion; from this it can be reasonably concluded that these were cases of misdiagnosed delirious mania.

Delirium hypothesis. Patients with delirious mania typically have features of delirium, including fluctuation of consciousness, disorientation, and/or poor sleep-wake cycle.³⁶ During rapid eye movement (REM) and non-REM sleep, memory circuits are fortified. When there is a substantial loss of REM and non-REM sleep, these circuits become faulty, even after 1 night. Pathological brain waves on EEG reflect the inability to reinforce the memory circuits. Patients with these waves may develop hallucinations, bizarre delusions, and altered sensorium. ECT reduces the pathological slow wave morphologies, thus restoring the synaptic maintenance and correcting the incompetent circuitry. This can explain the robust and rapid response of ECT in a patient with delirious mania.^37,38

Neurotransmitter hypothesis. It has been shown that in patients with delirious mania there is dysregulation of dopamine transport, which leads to dopamine overflow in the synapse. In contrast to a drug effect (ie, cocaine or methamphetamine) that acts by inhibiting dopamine reuptake, dopamine overflow in delirious mania is caused by the loss of dopamine transporter regulation. This results in a dysfunctional dopaminergic state that precipitates an acute state of delirium and agitation.^39,40

Serotonin plays a role in mood disorders, including mania and depression.^41,42 More specifically, serotonin has been implicated in impulsivity and aggression as shown by reduced levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) and depletion of 5-hydroxytryptophan (5-HTP).⁴³

Continue to: Alterations in gamma-aminobutyric acid (GABA) transmission...

Alterations in gamma-aminobutyric acid (GABA) transmission are known to occur in delirium and catatonia. In delirium, GABA signaling is increased, which disrupts the circadian rhythm and melatonin release, thus impairing the sleep-wake cycle.⁴⁴ Deficiencies in acetylcholine and melatonin are seen as well as excess of other neurotransmitters, including norepinephrine and glutamate.⁴⁵ Conversely, in catatonia, functional imaging studies found decreased GABA-A binding in orbito­frontal, prefrontal, parietal, and motor cortical regions.⁴⁶ A study analyzing 10 catatonic patients found decreased density of GABA-A receptors in the left sensorimotor cortex compared to psychiatric and healthy controls.⁴⁷

Other neurotransmitters, such as glutamate, at the N-methyl-D-aspartate receptors (NMDAR) have been hypothesized to be hyperactive, causing downstream dysregulation of GABA functioning.⁴⁸ However, the exact connection between delirious mania and all these receptors and neurotransmitters remains unknown.

Encephalitis hypothesis. The relationship between delirious mania and autoimmune encephalitis suggests delirious mania has etiologies other than a primary psychiatric illness. In a 2020 retrospective study⁴⁹ that analyzed 79 patients with anti-NMDAR encephalitis, 25.3% met criteria for delirious mania, and 95% of these patients had catatonic features. Dalmau et al⁵⁰ found that in many cases, patients tend to respond to ECT; in a cases series of 3 patients, 2 responded to benzodiazepines.

COVID-19 hypothesis. The SARS-CoV-2 virion has been associated with many neuropsychiatric complications, including mood, psychotic, and neurocognitive disorders.^51,52 There also have been cases of COVID-19–induced catatonia.^53-55 One case of delirious mania in a patient with COVID-19 has been reported.²¹ The general mechanism has been proposed to be related to the stimulation of the proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, which the virus produces in large quantities.⁵⁶ These cytokines have been linked to psychosis and other psychiatric disorders.⁵⁷ The patient with COVID-19–induced delirious mania had elevated inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, ferritin, and D-dimer, which supports a proinflammatory state. This patient had a complete resolution of symptoms with ECT.²¹

Management: Benzodiazepines and ECT

A step-by-step algorithm for managing delirious mania is outlined in the Figure. Regardless of the underlining etiology, management of delirious mania consists of benzodiazepines (lorazepam and diazepam); prompt use of ECT, particularly for patients who do not improve with large doses of lorazepam; or (if applicable) continued treatment of the underlining medical condition, which does not preclude the use of benzodiazepines or ECT. Recent reports^27,58 have described details for using ECT for delirious mania, highlighting the use of high-energy dosing, bilateral electrode placement, and frequent sessions.

Continue to: Knowing which medications...

Knowing which medications to avoid is as important as knowing which agents to administer. Be vigilant in avoiding high-potency antipsychotics, as these medications can worsen extrapyramidal symptoms and may precipitate seizures or neuroleptic malignant syndrome (NMS).²⁸ Anticholinergic agents should also be avoided because they worsen confusion. Although lithium is effective in BD, in delirious mania, high doses of lithium and haloperidol may cause severe encephalopathic syndromes, with symptoms that can include lethargy, tremors, cerebellar dysfunction, and worsened confusion; it may also cause widespread and irreversible brain damage.⁵⁹While positive outcomes have been documented when using a combination of antipsychotics and lithium,^8,60 this approach should be considered carefully and tailored to individual cases, taking into account the severity of manic and psychotic symptoms in addition to the level of catatonia.

Due to long periods of hyperactivity, withdrawal, and diaphoresis, patients with delirious mania may be severely dehydrated with metabolic derangements, including elevated CPK due to rhabdomyolysis from prolonged exertion, IM antipsychotics, or rigidity. To prevent acute renal failure, this must be immediately addressed with rapid fluid resuscitation and electrolyte repletion.⁶¹

Benzodiazepines. The rapid use of lorazepam should be initiated when delirious mania is suspected. Doses of 6 to 20 mg have been reported to be effective if tolerated.^5,20 Typically, high-dose lorazepam will not have the sedative effect that would normally occur in a patient who does not have delirious mania.² Lorazepam should be titrated until full resolution of symptoms. Doses up to 30 mg have been reported as effective and tolerable.⁶² In our literature review, 50% of patients (18/36) responded or partially responded to lorazepam. However, only 3 case reports documented a complete remission with lorazepam, and many patients needed ECT for remission of symptoms.

ECT is generally reserved for patients who are not helped by benzodiazepine therapy, which is estimated to be up to 20%.⁵ ECT is highly effective in delirious mania, with remission rates ranging from 80% to 100%.¹ ECT is also effective in acute non­delirious mania (comparable to depression); however, it is only used in a small minority of cases (0.2% to 12%).³⁵ In our review, 58% of cases (21/36) reported using ECT, and in all cases it resulted in complete remission.

A dramatic improvement can be seen even after a single ECT session, though most patients show improvement after 4 sessions or 3 to 7 days.^1,2,5 In our review, most patients received 4 to 12 sessions until achieving complete remission.

Continue to: No RCTs have evaluated...

No RCTs have evaluated ECT electrode placement in patients with delirious mania. However, several RCTs have investigated electrode placement in patients with acute nondelirious mania. Hiremani et al⁶³ found that bitemporal placement had a more rapid response rate than bifrontal placement, but there was no overall difference in response rate. Barekatain et al⁶⁴ found no difference between these 2 bilateral approaches. Many of the delirious mania cases report using a bilateral placement (including 42% of the ECT cases in our review) due to the emergent need for rapid relief of symptoms, which is especially necessary if the patient is experiencing hemodynamic instability, excessive violence, risk for self-harm, worsening delirium, or resistance to lorazepam.

Prognosis: Often fatal if left untreated

Patients with delirious mania are at high risk to progress to a more severe form of NMS or malignant catatonia. Therefore, high-potency antipsychotics should be avoided; mortality can be elevated from 60% without antipsychotics to 78% with antipsychotics.⁴ Some researchers estimate 75% to 78% of cases of delirious mania can be fatal if left untreated.^3,6

Bottom Line

Delirious mania is routinely mistaken for more conventional manic or psychotic disorders. Clinicians need to be able to rapidly recognize the symptoms of this syndrome, which include mania, psychosis, delirium, and possible catatonia, so they can avoid administering toxic agents and instead initiate effective treatments such as benzodiazepines and electroconvulsive therapy.

Related Resources

• Arsan C, Baker C, Wong J, et al. Delirious mania: an approach to diagnosis and treatment. Prim Care Companion CNS Disord. 2021;23(1):20f02744. doi:10.4088/PCC.20f02744
• Lamba G, Kennedy EA, Vu CP. Case report: ECT for delirious mania. Clinical Psychiatry News. December 14, 2021. https://www.mdedge.com/psychiatry/article/249909/bipolar-disorder/case-report-ect-delirious-mania

Drug Brand Names

Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan

Delirious mania is a syndrome characterized by the acute onset of severe hyperactivity, psychosis, catatonia, and intermittent confusion. While there have been growing reports of this phenomenon over the last 2 decades, it remains poorly recognized and understood.^1,2 There is no widely accepted nosology for delirious mania and the condition is absent from DSM-5, which magnifies the difficulties in making a timely diagnosis and initiating appropriate treatment. Delayed diagnosis and treatment may result in a detrimental outcome.^2,3 Delirious mania has also been labeled as lethal catatonia, specific febrile delirium, hyperactive or exhaustive mania, and Bell’s mania.^2,4,5 The characterization and diagnosis of this condition have a long and inconsistent history (Box^1,6-11).

Box

Delirious mania continues to be met with incertitude in clinical practice, and numerous inconsistencies have been reported in the literature. For example, some cases that have been reported as delirious mania had more evidence of primary delirium due to another medical condition or primary mania.^12,13 Other cases have demonstrated swift improvement of symptoms after monotherapy with antipsychotics without a trial of benzodiazepines or electroconvulsive therapy (ECT); the exclusion of a sudden onset questions the validity of the diagnosis and promotes the use of less efficacious treatments.^14,15 Other reports have confirmed that the diagnosis is missed when certain symptoms are more predominant, such as a thought disorder (acute schizophrenia), grandiosity and delusional ideation (bipolar disorder [BD]), and less commonly assessed catatonic signs (ambitendency, automatic obedience). These symptoms are mistakenly attributed to the respective disease.^1,16 This especially holds true when delirious mania is initially diagnosed as a primary psychosis, which leads to the administration of antipsychotics.¹⁷ Other cases have reported that delirious mania was resistant to treatment, but ECT was never pursued.¹⁸

In this review, we provide a more comprehensive perspective of the clinical presentation, pathogenesis, and management of delirious mania. We searched PubMed and Google Scholar using the keywords “delirious mania,” “delirious mania AND catatonia,” or “manic delirium.” Most articles we found were case reports, case series, or retrospective chart reviews. There were no systematic reviews, meta analyses, or randomized control trials (RCTs). The 12 articles included in this review consist of 7 individual case reports, 4 case series, and 1 retrospective chart review that describe a total of 36 cases (Table^{1,2,5,17,19-26}).

Clinical presentation: What to look for

Patients with delirious mania typically develop symptoms extremely rapidly. In virtually all published literature, symptoms were reported to emerge within hours to days and consisted of severe forms of mania, psychosis, and delirium; 100% of the cases in our review had these symptoms. Commonly reported symptoms were:

• intense excitement
• emotional lability
• grandiose delusions
• profound insomnia
• pressured and rapid speech
• auditory and visual hallucinations
• hypersexuality
• thought disorganization.

Exquisite paranoia can also result in violent aggression (and may require the use of physical restraints). Patients may confine themselves to very small spaces (such as a closet) in response to the intense paranoia. Impairments in various neurocognitive domains—including inability to focus; disorientation; language and visuospatial disturbances; difficulty with shifting and sustaining attention; and short-term memory impairments—have been reported. Patients often cannot recall the events during the episode.^1,2,5,27,28

Catatonia has been closely associated with delirious mania.²⁹ Features of excited catatonia—such as excessive motor activity, negativism, grimacing, posturing, echolalia, echopraxia, stereotypy, automatic obedience, verbigeration, combativeness, impulsivity, and rigidity—typically accompany delirious mania.^1,5,10,19,27

In addition to these symptoms, patients may engage in specific behaviors. They may exhibit inappropriate toileting such as smearing feces on walls or in bags, fecal or urinary incontinence, disrobing or running naked in public places, or pouring liquid on the floor or on one’s head.^1,2

Continue to: Of the 36 cases...

Of the 36 cases reported in the literature we reviewed, 20 (55%) were female. Most patients had an underlining psychiatric condition, including BD (72%), major depressive disorder (8%), and schizophrenia (2%). Three patients had no psychiatric history.

Physical examination

On initial presentation, a patient with delirious mania may be dehydrated, with dry mucous membranes, pale conjunctiva, tongue dryness, and poor skin turgor.^28,30 Due to excessive motor activity, diaphoresis with tachycardia, fluctuating blood pressure, and fever may be present.³¹

Certain basic cognitive tasks should be assessed to determine the patient’s orientation to place, date, and time. Assess if the patient can recall recent events, names of objects, or perform serial 7s; clock drawing capabilities also should be ascertained.^1,2,5 A Mini-Mental State Examination is useful.³²

The Bush-Francis Catatonia Rating Scale should be used to elicit features of catatonia, such as waxy flexibility, negativism, gegenhalten, mitgehen, catalepsy, ambitendency, automatic obedience, and grasp reflex.¹⁰

Laboratory findings are nonspecific

Although no specific laboratory findings are associated with delirious mania, bloodwork and imaging are routinely investigated, especially if delirium characteristics are most striking. A complete blood count, chemistries, hepatic panel, thyroid functioning, blood and/or urine cultures, creatinine phosphokinase (CPK), and urinalysis can be ordered. Head imaging such as MRI and CT to rule out intracranial pathology are typically performed.¹⁹ However, the diagnosis of delirious mania is based on the presence of the phenotypic features, by verification of catatonia, and by the responsiveness to the treatment delivered.²⁹

Continue to: Pathogenisis: Several hypotheses

The pathogenesis of delirious mania is not well understood. There are several postulations but no salient theory. Most patients with delirious mania have an underlying systemic medical or psychiatric condition.

Mood disorders. Patients with BD or schizoaffective disorder are especially susceptible to delirious mania. The percentage of manic patients who present with delirious mania varies by study. One study suggested approximately 19% have features of the phenomenon,³³ while others estimated 15% to 25%.³⁴ Elias et al³⁵ calculated that 15% of patients with mania succumb to manic exhaustion; from this it can be reasonably concluded that these were cases of misdiagnosed delirious mania.

Delirium hypothesis. Patients with delirious mania typically have features of delirium, including fluctuation of consciousness, disorientation, and/or poor sleep-wake cycle.³⁶ During rapid eye movement (REM) and non-REM sleep, memory circuits are fortified. When there is a substantial loss of REM and non-REM sleep, these circuits become faulty, even after 1 night. Pathological brain waves on EEG reflect the inability to reinforce the memory circuits. Patients with these waves may develop hallucinations, bizarre delusions, and altered sensorium. ECT reduces the pathological slow wave morphologies, thus restoring the synaptic maintenance and correcting the incompetent circuitry. This can explain the robust and rapid response of ECT in a patient with delirious mania.^37,38

Neurotransmitter hypothesis. It has been shown that in patients with delirious mania there is dysregulation of dopamine transport, which leads to dopamine overflow in the synapse. In contrast to a drug effect (ie, cocaine or methamphetamine) that acts by inhibiting dopamine reuptake, dopamine overflow in delirious mania is caused by the loss of dopamine transporter regulation. This results in a dysfunctional dopaminergic state that precipitates an acute state of delirium and agitation.^39,40

Serotonin plays a role in mood disorders, including mania and depression.^41,42 More specifically, serotonin has been implicated in impulsivity and aggression as shown by reduced levels of CSF 5-hydroxyindoleacetic acid (5-HIAA) and depletion of 5-hydroxytryptophan (5-HTP).⁴³

Continue to: Alterations in gamma-aminobutyric acid (GABA) transmission...

Alterations in gamma-aminobutyric acid (GABA) transmission are known to occur in delirium and catatonia. In delirium, GABA signaling is increased, which disrupts the circadian rhythm and melatonin release, thus impairing the sleep-wake cycle.⁴⁴ Deficiencies in acetylcholine and melatonin are seen as well as excess of other neurotransmitters, including norepinephrine and glutamate.⁴⁵ Conversely, in catatonia, functional imaging studies found decreased GABA-A binding in orbito­frontal, prefrontal, parietal, and motor cortical regions.⁴⁶ A study analyzing 10 catatonic patients found decreased density of GABA-A receptors in the left sensorimotor cortex compared to psychiatric and healthy controls.⁴⁷

Other neurotransmitters, such as glutamate, at the N-methyl-D-aspartate receptors (NMDAR) have been hypothesized to be hyperactive, causing downstream dysregulation of GABA functioning.⁴⁸ However, the exact connection between delirious mania and all these receptors and neurotransmitters remains unknown.

Encephalitis hypothesis. The relationship between delirious mania and autoimmune encephalitis suggests delirious mania has etiologies other than a primary psychiatric illness. In a 2020 retrospective study⁴⁹ that analyzed 79 patients with anti-NMDAR encephalitis, 25.3% met criteria for delirious mania, and 95% of these patients had catatonic features. Dalmau et al⁵⁰ found that in many cases, patients tend to respond to ECT; in a cases series of 3 patients, 2 responded to benzodiazepines.

COVID-19 hypothesis. The SARS-CoV-2 virion has been associated with many neuropsychiatric complications, including mood, psychotic, and neurocognitive disorders.^51,52 There also have been cases of COVID-19–induced catatonia.^53-55 One case of delirious mania in a patient with COVID-19 has been reported.²¹ The general mechanism has been proposed to be related to the stimulation of the proinflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, which the virus produces in large quantities.⁵⁶ These cytokines have been linked to psychosis and other psychiatric disorders.⁵⁷ The patient with COVID-19–induced delirious mania had elevated inflammatory markers, including erythrocyte sedimentation rate, C-reactive protein, ferritin, and D-dimer, which supports a proinflammatory state. This patient had a complete resolution of symptoms with ECT.²¹

Management: Benzodiazepines and ECT

A step-by-step algorithm for managing delirious mania is outlined in the Figure. Regardless of the underlining etiology, management of delirious mania consists of benzodiazepines (lorazepam and diazepam); prompt use of ECT, particularly for patients who do not improve with large doses of lorazepam; or (if applicable) continued treatment of the underlining medical condition, which does not preclude the use of benzodiazepines or ECT. Recent reports^27,58 have described details for using ECT for delirious mania, highlighting the use of high-energy dosing, bilateral electrode placement, and frequent sessions.

Continue to: Knowing which medications...

Knowing which medications to avoid is as important as knowing which agents to administer. Be vigilant in avoiding high-potency antipsychotics, as these medications can worsen extrapyramidal symptoms and may precipitate seizures or neuroleptic malignant syndrome (NMS).²⁸ Anticholinergic agents should also be avoided because they worsen confusion. Although lithium is effective in BD, in delirious mania, high doses of lithium and haloperidol may cause severe encephalopathic syndromes, with symptoms that can include lethargy, tremors, cerebellar dysfunction, and worsened confusion; it may also cause widespread and irreversible brain damage.⁵⁹While positive outcomes have been documented when using a combination of antipsychotics and lithium,^8,60 this approach should be considered carefully and tailored to individual cases, taking into account the severity of manic and psychotic symptoms in addition to the level of catatonia.

Due to long periods of hyperactivity, withdrawal, and diaphoresis, patients with delirious mania may be severely dehydrated with metabolic derangements, including elevated CPK due to rhabdomyolysis from prolonged exertion, IM antipsychotics, or rigidity. To prevent acute renal failure, this must be immediately addressed with rapid fluid resuscitation and electrolyte repletion.⁶¹

Benzodiazepines. The rapid use of lorazepam should be initiated when delirious mania is suspected. Doses of 6 to 20 mg have been reported to be effective if tolerated.^5,20 Typically, high-dose lorazepam will not have the sedative effect that would normally occur in a patient who does not have delirious mania.² Lorazepam should be titrated until full resolution of symptoms. Doses up to 30 mg have been reported as effective and tolerable.⁶² In our literature review, 50% of patients (18/36) responded or partially responded to lorazepam. However, only 3 case reports documented a complete remission with lorazepam, and many patients needed ECT for remission of symptoms.

ECT is generally reserved for patients who are not helped by benzodiazepine therapy, which is estimated to be up to 20%.⁵ ECT is highly effective in delirious mania, with remission rates ranging from 80% to 100%.¹ ECT is also effective in acute non­delirious mania (comparable to depression); however, it is only used in a small minority of cases (0.2% to 12%).³⁵ In our review, 58% of cases (21/36) reported using ECT, and in all cases it resulted in complete remission.

A dramatic improvement can be seen even after a single ECT session, though most patients show improvement after 4 sessions or 3 to 7 days.^1,2,5 In our review, most patients received 4 to 12 sessions until achieving complete remission.

Continue to: No RCTs have evaluated...

No RCTs have evaluated ECT electrode placement in patients with delirious mania. However, several RCTs have investigated electrode placement in patients with acute nondelirious mania. Hiremani et al⁶³ found that bitemporal placement had a more rapid response rate than bifrontal placement, but there was no overall difference in response rate. Barekatain et al⁶⁴ found no difference between these 2 bilateral approaches. Many of the delirious mania cases report using a bilateral placement (including 42% of the ECT cases in our review) due to the emergent need for rapid relief of symptoms, which is especially necessary if the patient is experiencing hemodynamic instability, excessive violence, risk for self-harm, worsening delirium, or resistance to lorazepam.

Prognosis: Often fatal if left untreated

Patients with delirious mania are at high risk to progress to a more severe form of NMS or malignant catatonia. Therefore, high-potency antipsychotics should be avoided; mortality can be elevated from 60% without antipsychotics to 78% with antipsychotics.⁴ Some researchers estimate 75% to 78% of cases of delirious mania can be fatal if left untreated.^3,6

Bottom Line

Delirious mania is routinely mistaken for more conventional manic or psychotic disorders. Clinicians need to be able to rapidly recognize the symptoms of this syndrome, which include mania, psychosis, delirium, and possible catatonia, so they can avoid administering toxic agents and instead initiate effective treatments such as benzodiazepines and electroconvulsive therapy.

Related Resources

• Arsan C, Baker C, Wong J, et al. Delirious mania: an approach to diagnosis and treatment. Prim Care Companion CNS Disord. 2021;23(1):20f02744. doi:10.4088/PCC.20f02744
• Lamba G, Kennedy EA, Vu CP. Case report: ECT for delirious mania. Clinical Psychiatry News. December 14, 2021. https://www.mdedge.com/psychiatry/article/249909/bipolar-disorder/case-report-ect-delirious-mania

Drug Brand Names

Diazepam • Valium
Haloperidol • Haldol
Lithium • Eskalith, Lithobid
Lorazepam • Ativan

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.

The second-generation antipsychotic quetiapine is commonly used to treat several psychiatric disorders, including bipolar disorder (BD) and insomnia. In this case report, we discuss a patient with a history of unipolar depression and initial signs of mania who experienced an exacerbation of manic symptoms following administration of low-dose quetiapine. This case underscores the need for careful monitoring of patients receiving quetiapine, especially at lower doses, and the potential limitations of its efficacy in controlling manic symptoms.

Depressed with racing thoughts

Mr. X, age 58, is an Army veteran who lives with his wife of 29 years and works as a contractor. He has a history of depression and a suicide attempt 10 years ago by self-inflicted gunshot wound to the head, which left him with a bullet lodged in his sinus cavity and residual dysarthria after tongue surgery. After the suicide attempt, Mr. X was medically hospitalized, but not psychiatrically hospitalized. Shortly after, he self-discontinued all psychotropic medications and follow-up.

Mr. X has no other medical history and takes no other medications or supplements. His family history includes a mother with schizoaffective disorder, 1 brother with BD, and another brother with developmental delay.

Mr. X remained euthymic until his brother died. Soon after, he began to experience low mood, heightened anxiety, racing thoughts, tearfulness, and mild insomnia. He was prescribed quetiapine 25 mg/d at bedtime and instructed to titrate up to 50 mg/d.

Ten days later, Mr. X was brought to the hospital by his wife, who reported that after starting quetiapine, her husband began to act erratically. He had disorganized and racing thoughts, loose associations, labile affect, hyperactivity/restlessness, and was not sleeping. In the morning before presenting to the hospital, Mr. X had gone to work, laid down on the floor, began mumbling to himself, and would not respond to coworkers. Upon evaluation, Mr. X was noted to have pressured speech, disorganized speech, delusions, anxiety, and hallucinations. A CT scan of his head was normal, and a complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone, B12, folate, and hemoglobin A1c were within normal limits. Mr. X’s vitamin D level was low at 22 ng/mL, and a syphilis screen was negative.

Mr. X was admitted to the hospital for his safety. The treatment team discontinued quetiapine and started risperidone 3 mg twice a day for psychotic symptoms and mood stabilization. At the time of discharge 7 days later, Mr. X was no longer experiencing any hallucinations or delusions, his thought process was linear and goal-directed, his mood was stable, and his insomnia had improved. Based on the temporal relationship between the initiation of quetiapine and the onset of Mr. X’s manic symptoms, along with an absence of organic causes, the treatment team suspected Mr. X had experienced a worsening of manic symptoms induced by quetiapine. Before starting quetiapine, he had presented with an initial manic symptom of racing thoughts.

At his next outpatient appointment, Mr. X exhibited significant akathisia. The treatment team initiated propranolol 20 mg twice a day but Mr. X did not experience much improvement. Risperidone was reduced to 1 mg twice a day and Mr. X was started on clonazepam 0.5 mg twice a day. The akathisia resolved. The treatment team decided to discontinue all medications and observe Mr. X for any recurrence of symptoms. One year after his manic episode. Mr. X remained euthymic. He was able to resume full-time work and began psychotherapy to process the grief over the loss of his brother.

Quetiapine’s unique profile

This case sheds light on the potential limitations of quetiapine, especially at lower doses, for managing manic symptoms. Quetiapine exhibits antidepressant effects, even at doses as low as 50 mg/d.¹ At higher doses, quetiapine acts as an antagonist at serotonin (5-HT1A and 5-HT2A), dopamine (D1 and D2), histamine H1, and adrenergic receptors.² At doses <300 mg/d, there is an absence of dopamine receptor blockade and a higher affinity for 5-HT2A receptors, which could explain why higher doses are generally necessary for treating mania and psychotic symptoms.^3-5 High 5-HT2A antagonism may disinhibit the dopaminergic system and paradoxically increase dopaminergic activity, which could be the mechanism responsible for lack of control of manic symptoms with low doses of quetiapine.² Another possible explanation is that the metabolite of quetiapine, N-desalkylquetiapine, acts as a norepine­phrine reuptake blocker and partial 5-HT1Aantagonist, which acts as an antidepressant, and antidepressants are known to induce mania in vulnerable patients.⁴

The antimanic property of most antipsychotics (except possibly clozapine) is attributed to their D2 antagonistic potency. Because quetiapine is among the weaker D2 antagonists, its inability to prevent the progression of mania, especially at 50 mg/d, is not unexpected. Mr. X’s subsequent need for a stronger D2 antagonist—risperidone—at a significant dose further supports this observation. A common misconception is that quetiapine’s sedating effects make it effective for treating mania, but that is not the case. Clinicians should be cautious when prescribing quetiapine, especially at lower doses, to patients who exhibit signs of mania. Given the potential risk, clinicians should consider alternative treatments before resorting to low-dose quetiapine for insomnia. Regular monitoring for manic symptoms is crucial for all patients receiving quetiapine. If patients present with signs of mania or hypomania, a therapeutic dose range of 600 to 800 mg/d is recommended.⁶

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.

The second-generation antipsychotic quetiapine is commonly used to treat several psychiatric disorders, including bipolar disorder (BD) and insomnia. In this case report, we discuss a patient with a history of unipolar depression and initial signs of mania who experienced an exacerbation of manic symptoms following administration of low-dose quetiapine. This case underscores the need for careful monitoring of patients receiving quetiapine, especially at lower doses, and the potential limitations of its efficacy in controlling manic symptoms.

Depressed with racing thoughts

Mr. X, age 58, is an Army veteran who lives with his wife of 29 years and works as a contractor. He has a history of depression and a suicide attempt 10 years ago by self-inflicted gunshot wound to the head, which left him with a bullet lodged in his sinus cavity and residual dysarthria after tongue surgery. After the suicide attempt, Mr. X was medically hospitalized, but not psychiatrically hospitalized. Shortly after, he self-discontinued all psychotropic medications and follow-up.

Mr. X has no other medical history and takes no other medications or supplements. His family history includes a mother with schizoaffective disorder, 1 brother with BD, and another brother with developmental delay.

Mr. X remained euthymic until his brother died. Soon after, he began to experience low mood, heightened anxiety, racing thoughts, tearfulness, and mild insomnia. He was prescribed quetiapine 25 mg/d at bedtime and instructed to titrate up to 50 mg/d.

Ten days later, Mr. X was brought to the hospital by his wife, who reported that after starting quetiapine, her husband began to act erratically. He had disorganized and racing thoughts, loose associations, labile affect, hyperactivity/restlessness, and was not sleeping. In the morning before presenting to the hospital, Mr. X had gone to work, laid down on the floor, began mumbling to himself, and would not respond to coworkers. Upon evaluation, Mr. X was noted to have pressured speech, disorganized speech, delusions, anxiety, and hallucinations. A CT scan of his head was normal, and a complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone, B12, folate, and hemoglobin A1c were within normal limits. Mr. X’s vitamin D level was low at 22 ng/mL, and a syphilis screen was negative.

Mr. X was admitted to the hospital for his safety. The treatment team discontinued quetiapine and started risperidone 3 mg twice a day for psychotic symptoms and mood stabilization. At the time of discharge 7 days later, Mr. X was no longer experiencing any hallucinations or delusions, his thought process was linear and goal-directed, his mood was stable, and his insomnia had improved. Based on the temporal relationship between the initiation of quetiapine and the onset of Mr. X’s manic symptoms, along with an absence of organic causes, the treatment team suspected Mr. X had experienced a worsening of manic symptoms induced by quetiapine. Before starting quetiapine, he had presented with an initial manic symptom of racing thoughts.

At his next outpatient appointment, Mr. X exhibited significant akathisia. The treatment team initiated propranolol 20 mg twice a day but Mr. X did not experience much improvement. Risperidone was reduced to 1 mg twice a day and Mr. X was started on clonazepam 0.5 mg twice a day. The akathisia resolved. The treatment team decided to discontinue all medications and observe Mr. X for any recurrence of symptoms. One year after his manic episode. Mr. X remained euthymic. He was able to resume full-time work and began psychotherapy to process the grief over the loss of his brother.

Quetiapine’s unique profile

This case sheds light on the potential limitations of quetiapine, especially at lower doses, for managing manic symptoms. Quetiapine exhibits antidepressant effects, even at doses as low as 50 mg/d.¹ At higher doses, quetiapine acts as an antagonist at serotonin (5-HT1A and 5-HT2A), dopamine (D1 and D2), histamine H1, and adrenergic receptors.² At doses <300 mg/d, there is an absence of dopamine receptor blockade and a higher affinity for 5-HT2A receptors, which could explain why higher doses are generally necessary for treating mania and psychotic symptoms.^3-5 High 5-HT2A antagonism may disinhibit the dopaminergic system and paradoxically increase dopaminergic activity, which could be the mechanism responsible for lack of control of manic symptoms with low doses of quetiapine.² Another possible explanation is that the metabolite of quetiapine, N-desalkylquetiapine, acts as a norepine­phrine reuptake blocker and partial 5-HT1Aantagonist, which acts as an antidepressant, and antidepressants are known to induce mania in vulnerable patients.⁴

The antimanic property of most antipsychotics (except possibly clozapine) is attributed to their D2 antagonistic potency. Because quetiapine is among the weaker D2 antagonists, its inability to prevent the progression of mania, especially at 50 mg/d, is not unexpected. Mr. X’s subsequent need for a stronger D2 antagonist—risperidone—at a significant dose further supports this observation. A common misconception is that quetiapine’s sedating effects make it effective for treating mania, but that is not the case. Clinicians should be cautious when prescribing quetiapine, especially at lower doses, to patients who exhibit signs of mania. Given the potential risk, clinicians should consider alternative treatments before resorting to low-dose quetiapine for insomnia. Regular monitoring for manic symptoms is crucial for all patients receiving quetiapine. If patients present with signs of mania or hypomania, a therapeutic dose range of 600 to 800 mg/d is recommended.⁶

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.

The second-generation antipsychotic quetiapine is commonly used to treat several psychiatric disorders, including bipolar disorder (BD) and insomnia. In this case report, we discuss a patient with a history of unipolar depression and initial signs of mania who experienced an exacerbation of manic symptoms following administration of low-dose quetiapine. This case underscores the need for careful monitoring of patients receiving quetiapine, especially at lower doses, and the potential limitations of its efficacy in controlling manic symptoms.

Depressed with racing thoughts

Mr. X, age 58, is an Army veteran who lives with his wife of 29 years and works as a contractor. He has a history of depression and a suicide attempt 10 years ago by self-inflicted gunshot wound to the head, which left him with a bullet lodged in his sinus cavity and residual dysarthria after tongue surgery. After the suicide attempt, Mr. X was medically hospitalized, but not psychiatrically hospitalized. Shortly after, he self-discontinued all psychotropic medications and follow-up.

Mr. X has no other medical history and takes no other medications or supplements. His family history includes a mother with schizoaffective disorder, 1 brother with BD, and another brother with developmental delay.

Mr. X remained euthymic until his brother died. Soon after, he began to experience low mood, heightened anxiety, racing thoughts, tearfulness, and mild insomnia. He was prescribed quetiapine 25 mg/d at bedtime and instructed to titrate up to 50 mg/d.

Ten days later, Mr. X was brought to the hospital by his wife, who reported that after starting quetiapine, her husband began to act erratically. He had disorganized and racing thoughts, loose associations, labile affect, hyperactivity/restlessness, and was not sleeping. In the morning before presenting to the hospital, Mr. X had gone to work, laid down on the floor, began mumbling to himself, and would not respond to coworkers. Upon evaluation, Mr. X was noted to have pressured speech, disorganized speech, delusions, anxiety, and hallucinations. A CT scan of his head was normal, and a complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone, B12, folate, and hemoglobin A1c were within normal limits. Mr. X’s vitamin D level was low at 22 ng/mL, and a syphilis screen was negative.

Mr. X was admitted to the hospital for his safety. The treatment team discontinued quetiapine and started risperidone 3 mg twice a day for psychotic symptoms and mood stabilization. At the time of discharge 7 days later, Mr. X was no longer experiencing any hallucinations or delusions, his thought process was linear and goal-directed, his mood was stable, and his insomnia had improved. Based on the temporal relationship between the initiation of quetiapine and the onset of Mr. X’s manic symptoms, along with an absence of organic causes, the treatment team suspected Mr. X had experienced a worsening of manic symptoms induced by quetiapine. Before starting quetiapine, he had presented with an initial manic symptom of racing thoughts.

At his next outpatient appointment, Mr. X exhibited significant akathisia. The treatment team initiated propranolol 20 mg twice a day but Mr. X did not experience much improvement. Risperidone was reduced to 1 mg twice a day and Mr. X was started on clonazepam 0.5 mg twice a day. The akathisia resolved. The treatment team decided to discontinue all medications and observe Mr. X for any recurrence of symptoms. One year after his manic episode. Mr. X remained euthymic. He was able to resume full-time work and began psychotherapy to process the grief over the loss of his brother.

Quetiapine’s unique profile

This case sheds light on the potential limitations of quetiapine, especially at lower doses, for managing manic symptoms. Quetiapine exhibits antidepressant effects, even at doses as low as 50 mg/d.¹ At higher doses, quetiapine acts as an antagonist at serotonin (5-HT1A and 5-HT2A), dopamine (D1 and D2), histamine H1, and adrenergic receptors.² At doses <300 mg/d, there is an absence of dopamine receptor blockade and a higher affinity for 5-HT2A receptors, which could explain why higher doses are generally necessary for treating mania and psychotic symptoms.^3-5 High 5-HT2A antagonism may disinhibit the dopaminergic system and paradoxically increase dopaminergic activity, which could be the mechanism responsible for lack of control of manic symptoms with low doses of quetiapine.² Another possible explanation is that the metabolite of quetiapine, N-desalkylquetiapine, acts as a norepine­phrine reuptake blocker and partial 5-HT1Aantagonist, which acts as an antidepressant, and antidepressants are known to induce mania in vulnerable patients.⁴

The antimanic property of most antipsychotics (except possibly clozapine) is attributed to their D2 antagonistic potency. Because quetiapine is among the weaker D2 antagonists, its inability to prevent the progression of mania, especially at 50 mg/d, is not unexpected. Mr. X’s subsequent need for a stronger D2 antagonist—risperidone—at a significant dose further supports this observation. A common misconception is that quetiapine’s sedating effects make it effective for treating mania, but that is not the case. Clinicians should be cautious when prescribing quetiapine, especially at lower doses, to patients who exhibit signs of mania. Given the potential risk, clinicians should consider alternative treatments before resorting to low-dose quetiapine for insomnia. Regular monitoring for manic symptoms is crucial for all patients receiving quetiapine. If patients present with signs of mania or hypomania, a therapeutic dose range of 600 to 800 mg/d is recommended.⁶