How an Understanding of the Function of the Locus Coeruleus Led to Use of Dexmedetomidine to Treat Agitation in Bipolar Disorder: Example of Rational Development of Psychiatric Medications

Preskorn, Sheldon

doi:10.1097/pra.0000000000000634

Cited by 9 publications

(6 citation statements)

References 32 publications

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“…The LC influences numerous parameters in the cardiovascular system, including cardiac output and peripheral resistance, which are essential in fight or flight reactions. The basis for this conclusion is the anatomy and physiology of the LC as summarized in an earlier column in this series 3…”

Section: The Role Of the Lcmentioning

confidence: 96%

“…The basis for this conclusion is the anatomy and physiology of the LC as summarized in an earlier column in this series. 3…”

Section: The Role Of the Lcmentioning

confidence: 99%

“…These points are also pertinent to the treatment of and drug development for many other psychiatric disorders. The publications are (1) a report on the results of a registration trial of the sublingual film formulation of sublingual dexmedetomidine (SLD) for the treatment of agitation in individuals with bipolar disorder published in the Journal of the American Medical Association (JAMA) in 20221; (2) the accepted but not yet published results of an identical trial of SLD in agitated individuals with schizophrenia2; and (3) a previous column in this journal outlining the results of a series of studies done to establish the functional role of the locus coeruleus (LC) in the brain, which is the target of SLD and several other drugs that are alpha-2 adrenergic agonists3; and (4) several unpublished human pharmacology studies done before the pivotal registration trials of SLD 4…”

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confidence: 99%

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Treatment of Agitation in Individuals With Bipolar Disorder or Schizophrenia: Lessons Learned for Clinical Psychiatry and Psychiatric Drug Development

Preskorn¹

2022

Journal of Psychiatric Practice

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Six lessons can be learned from the pivotal registration trials for sublingual dexmedetomidine (SLD) for the treatment of agitation in individuals with bipolar disorder or schizophrenia: (1) Knowing the function of a well-defined circuit in the brain, such as the locus coeruleus (LC), facilitates the development of central nervous system drugs. (2) Agitation can be conceptualized both clinically and physiologically. From both perspectives, agitation can present and escalate along a spectrum from mild, characterized as mainly hyperaroused (possibly only a subjective experience with no observable manifestations in its mildest form), to moderate to severe. In the severe state, the patient poses a potential danger to self and others. The level of agitation a patient is experiencing can determine the most appropriate treatment. Behavioral techniques may be sufficient for the mild state. As agitation progresses beyond mild severity, medication intervention becomes needed. SLD can be effective when agitation is moderate or even more severe. At this stage, patients can recognize and be distressed by their symptoms and participate in treatment. When agitation has escalated to such a severe state that patients can no longer participate in treatment, then intramuscular or intravenous medication may be needed. In quite severe cases, physical restraint as well as medication may be required. The Positive and Negative Syndrome Scale-Excited Component (PANSS-EC or PEC), a subscale of the PANSS, is a helpful instrument to assess where an individual is along the agitation spectrum. The PEC has been used in studies of pharmacological treatments for agitation, and it is accepted by the US Food and Drug Administration as the primary rating instrument in pivotal efficacy studies of treatments for agitation. (3) Where the patient is on the agitation spectrum is a function of the activity of the LC, which can be one factor in determining the SLD dose that will optimize the patient’s clinical outcome. Clinical outcome is optimized when complete resolution of agitation is rapidly achieved, and adverse effects either do not occur or are not clinically meaningful. The adverse effects of greatest interest with SLD are decreases in resting systolic and diastolic blood pressures, reductions in these blood pressures under orthostatic stress, and lower resting heart rate. (4) To ensure safety, the subjects in 2 healthy volunteer studies were not administered doses equivalent to those used to treat agitated patients. The highest dose which a healthy volunteer tolerated in those studies was 40 µg. Agitated patients were treated with 120 and 180 µg doses. Thus the difference in doses was 3- to 4.5-fold. Agitated patients could also receive 2 additional half doses with an interval of 2 hours between the first and second administrations. For context, there are other examples of situations in which the dose of a drug that is well tolerated by healthy volunteers is lower than the dose that is well tolerated by patients. For example, it has long been ac...

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Section: The Role Of the Lcmentioning

confidence: 96%

“…The basis for this conclusion is the anatomy and physiology of the LC as summarized in an earlier column in this series. 3…”

Section: The Role Of the Lcmentioning

confidence: 99%

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confidence: 99%

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Treatment of Agitation in Individuals With Bipolar Disorder or Schizophrenia: Lessons Learned for Clinical Psychiatry and Psychiatric Drug Development

Preskorn¹

2022

Journal of Psychiatric Practice

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“…Making that distinction would be resolved by measuring blood pressure and heart rate. Readers interested in more details on this question are referred to 2 recent columns 8,9…”

Section: Seven Mechanistically Different Classes Of Medications To Tr...mentioning

confidence: 99%

“…Readers interested in more details on this question are referred to 2 recent columns. 8,9 MT1 and MT2 Receptor Agonists Ramelteon is the only current member of this class that is indicated and used as a sleep enhancer. It acts on the PG feedback on SCN signaling.…”

Section: Caveat: Alpha-2 Ne Agonistsmentioning

confidence: 99%

Seven Mechanistically Different Classes of Medications Can Be Used to Treat Insomnia and Related Sleep Disorders

Preskorn

2023

Journal of Psychiatric Practice

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Over his 45-year career, S.H.P. has worked with over 145 pharmaceutical and biotech companies in the United States and throughout the world. Over the past year, he has received grants/research support from or has served as a consultant, on the advisory board, or on the speaker's bureau for Alkermes, BioXcel, Janssen, Otsuka, Relmada, and Usona Institute. All clinical trial and study contracts were with and payments made to the

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Letter to the editor: “Clonidine is associated with faster first resolution of incident ICU delirium than antipsychotics”

Quintin,

Ghignone

2024

Journal of Critical Care

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How an Understanding of the Function of the Locus Coeruleus Led to Use of Dexmedetomidine to Treat Agitation in Bipolar Disorder: Example of Rational Development of Psychiatric Medications

Cited by 9 publications

References 32 publications

Treatment of Agitation in Individuals With Bipolar Disorder or Schizophrenia: Lessons Learned for Clinical Psychiatry and Psychiatric Drug Development

Treatment of Agitation in Individuals With Bipolar Disorder or Schizophrenia: Lessons Learned for Clinical Psychiatry and Psychiatric Drug Development

Seven Mechanistically Different Classes of Medications Can Be Used to Treat Insomnia and Related Sleep Disorders

Letter to the editor: “Clonidine is associated with faster first resolution of incident ICU delirium than antipsychotics”

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