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

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 accepted that patients with an acute relapse of schizophrenia can tolerate and need higher doses of D2 antagonists for efficacy than healthy volunteers can tolerate who will generally experience substantial sedation if given what is a clinically effective dose in such patients. (5) Agitation is a state phenomenon that may not recur when it is effectively treated, so that the treatment effect can persist for 24 hours despite the plasma half-life of the drug being 2 to 3 hours. (6) Given the established function of the LC, the fact that the dose response and the time curve of the effect are virtually identical in agitated individuals with bipolar disorder or schizophrenia supports the conclusion that the drug is not treating the syndromic diagnoses of bipolar disorder and schizophrenia but rather the state of being agitated because of overactivity of the LC. These 6 lessons are consistent with the discussions in numerous earlier columns in this series and are critical for both the practice of clinical psychopharmacology and psychiatric drug development.