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Objective: This post hoc analysis evaluated the effect of lurasidone on agitation in acutely ill patients with schizophrenia., Method: Patient-level data were pooled from five 6-week, randomized, double-blind, placebo-controlled studies of fixed-dose, once-daily, oral lurasidone (40, 80, 120, or 160 mg/d). Agitation was assessed with the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score, utilizing a mixed model for repeated measurement analysis., Results: In patients with higher levels of agitation at baseline (PANSS-EC score≥14; n=773), lurasidone was associated with significantly greater improvement in least-squares (LS) mean PANSS-EC scores versus placebo at Day 3/4 (-1.6 vs -1.0; p<0.05), Day 7 (-2.3 vs -1.6; p<0.05), and at Week 6 endpoint (-5.5 vs -3.8; p<0.001; effect size=0.43). In patients with lower agitation at baseline (PANSS-EC score<14; n=754), LS mean PANSS-EC score change was significantly greater for lurasidone compared with placebo at Day 7 (-0.8 vs -0.1; p<0. 01) through Week 6 endpoint (-1.9 vs -0.9; p<0.001; effect size=0.31). Higher doses of lurasidone were notably more effective than lower doses in patients with more severe agitation at study baseline., Conclusion: In this pooled analysis of 5 short-term studies, lurasidone provided early and sustained reduction in agitation, assessed using the PANSS-EC score, in patients with an acute exacerbation of schizophrenia. Higher doses of lurasidone were particularly effective in patients with more severe agitation at study baseline. Overall, these results suggest that lurasidone may be a useful treatment option for patients exhibiting agitation associated with acute psychotic symptoms of schizophrenia. ClinicalTrials.gov Identifiers: NCT00088634 (Study D1050196); NCT00549718 (Study D1050229), NCT00615433 (Study D1050231); NCT00790192 (Study D1050233). Study D1050006 was completed prior to the requirement to register trials., (Copyright © 2017 Sunovion Pharmaceuticals Inc. Published by Elsevier Inc. All rights reserved.)

Background: Psychomotor agitation is associated with different psychiatric conditions and represents an important issue in psychiatry. Current recommendations on agitation in psychiatry are not univocal. Actually, an improper assessment and management may result in unnecessary coercive or sedative treatments. A thorough and balanced review plus an expert consensus can guide assessment and treatment decisions., Methods: An expert task force iteratively developed consensus using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new, re-worded or re-rated items., Results: Out of 2175 papers assessing psychomotor agitation, 124 were included in the review. Each component was assigned a level of evidence. Integrating the evidence and the experience of the task force members, a consensus was reached on 22 statements on this topic., Conclusions: Recommendations on the assessment of agitation emphasise the importance of identifying any possible medical cause. For its management, experts agreed in considering verbal de-escalation and environmental modification techniques as first choice, considering physical restraint as a last resort strategy. Regarding pharmacological treatment, the "ideal" medication should calm without over-sedate. Generally, oral or inhaled formulations should be preferred over i.m. routes in mildly agitated patients. Intravenous treatments should be avoided.

Psychomotor agitation is often associated with aggression. It is important to identify agitation early and achieve results quickly in order to prevent aggressive behavior. Strategies may include verbal de-escalation techniques, reduced stimulation, medications, or a combination of approaches. Historically, pharmacological treatments for agitation have been delivered using oral and intramuscular formulations. Although the types of medication available have not changed dramatically, different formulations have been developed recently to aid in treating this difficult condition. This paper will detail some of the newer, more novel formulations used to deliver medications to treat agitation. Formulations to be described include orally disintegrating tablets, sublingual, buccal and intranasal forms, as well as an inhalation form. Each form has a unique purpose and will aid in treatment of different populations at different levels of agitation. Of note, of the medication formulations to be discussed, only inhaled loxapine is FDA approved for acute agitation in schizophrenia and bipolar disorder and no medications are approved for 'agitation' outside of a specific disease state. The orally disintegrating tablets of olanzapine, risperidone, and aripiprazole are swallowed and enter the circulation via the portal system. They do not have a more rapid onset of action than the standard oral tablets but are useful for patients that might otherwise divert the medication. The sublingual, buccal and intranasal formulations include asenapine and midazolam. Absorption by this route is more rapid and avoids first-pass metabolism. Finally, inhaled loxapine enters the alveoli and appears quickly in the arterial circulation. All of these novel formulations require at least some cooperation but have the potential to prevent escalation and improve the experience of patients and could be considered when negotiation is possible.

Objective: The present study evaluated inhaled loxapine for the acute treatment of agitation in patients with bipolar I disorder., Methods: A Phase 3, randomized, double blind, placebo-controlled, parallel group inpatient study was performed at 17 psychiatric research facilities. Agitated patients (N=314) with bipolar I disorder (manic or mixed episodes) were randomized (1:1:1) to inhaled loxapine 5 mg or 10 mg, or inhaled placebo using the Staccato® system. Following baseline assessments, patients received Dose 1 and were evaluated for 24 hours. If required, up to two additional doses of study drug and/or lorazepam rescue medication were given. The primary efficacy endpoint was change from baseline in the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) score two hours after Dose 1. The key secondary endpoint was the Clinical Global Impression-Improvement score at two hours after Dose 1. Additional endpoints included the changes from baseline in the PANSS-EC from 10 min through 24 hours after Dose 1. Safety was assessed by adverse events, vital signs, physical examinations, and laboratory tests., Results: For the primary and key secondary endpoints, both doses of inhaled loxapine significantly reduced agitation compared with placebo. Reduced agitation, as reflected in PANSS-EC score, was evident 10 min after Dose 1 with both doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications (dysgeusia was reported in 17% of patients receiving active drug versus 6% receiving placebo)., Conclusions: Inhaled loxapine provided a rapid, non-injection, well-tolerated acute treatment for agitation in patients with bipolar I disorder., (© 2012 John Wiley and Sons A/S.)

Objective: The objective of this study was to assess the efficacy and safety of inhaled loxapine in the treatment of agitation in patients with psychotic disorders., Method: In this randomized, double-blind, placebo-controlled study, 129 agitated patients with schizophrenia or schizoaffective disorder (DSM-IV criteria) were randomized to receive in a clinical or hospital setting a single inhalation of 5 or 10 mg of loxapine or placebo administered using the Staccato loxapine for inhalation device. The inhalation device delivered thermally generated drug aerosol to the deep lung for rapid absorption. The primary efficacy measure was change on the Positive and Negative Syndrome Scale-excited component (PANSS-EC) 2 hours following treatment. Secondary outcomes included the Clinical Global Impressions-Improvement scale (CGI-I), Behavioral Activity Rating Scale (BARS), and time to first rescue medication. The study was conducted between September 2006 and January 2007., Results: Differences were statistically significant (P < .05) between placebo and both 5-mg and 10-mg doses on the CGI-I and the CGI-I responder analyses at 2 hours and in time to first rescue medication, and they were statistically significant (P < .05) between placebo and 10-mg loxapine on the PANSS-EC 20 minutes after administration continuing through 2 hours and in change from baseline BARS. Three serious adverse events occurred at least 6 days after treatment, but none were judged related to study treatment. The most common adverse events were sedation and dysgeusia (22% and 17%, respectively, in the 10-mg group, and 14% and 9%, respectively, in the placebo group)., Conclusions: Inhaled loxapine was generally safe and well tolerated and produced rapid improvement in agitated patients with psychotic disorders. Statistically significant differences in efficacy were found for the 10-mg dose compared with placebo, with results suggesting 5 mg may be effective. The delivery of loxapine by inhalation may provide a rapid, well-tolerated option for treating acute psychotic agitation that allows patients to avoid the aversive effects and loss of autonomy often associated with use of intramuscular medications. Further investigation of this new loxapine formulation is warranted., Trial Registration: ClinicalTrials.gov identifier: NCT00369577., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Background: There is a need for a rapid-acting, non-injection, acute treatment for agitation., Aims: To evaluate inhaled loxapine for acute treatment of agitation in schizophrenia., Method: This phase III, randomised, double-blind, placebo-controlled, parallel-group study (ClinicalTrials.gov number NCT00628589) enrolled 344 individuals who received one, two or three doses of inhaled loxapine (5 or 10 mg) or a placebo. Lorazepam rescue was permitted after dose two. The primary efficacy end-point was change from baseline in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) 2 h after dose one. The key secondary end-point was Clinical Global Impression-Improvement scale (CGI-I) score 2 h after dose one., Results: Inhaled loxapine (5 and 10 mg) significantly reduced agitation compared with placebo as assessed by primary and key secondary end-points. Reduced PANSS-EC score was evident 10 min after dose one with both 5 and 10 mg doses. Inhaled loxapine was well tolerated, and the most common adverse events were known effects of loxapine or minor oral effects common with inhaled medications., Conclusions: Inhaled loxapine provided a rapid, well-tolerated acute treatment for agitation in people with schizophrenia.

Background: Between 2001 and 2005 important changes were observed in expert opinion about the clinical management of patients with schizophrenia (SCZ) and agitation requiring an IM psychotropic, with a growing interest for IM atypical antipsychotics., Study Objectives: In an effort to acquire a typical, medically and psychiatrically unselected population of severely agitated patients with SCZ, we conducted a naturalistic study in an emergency setting, consecutively enrolling agitated patients who refused oral treatment., Method: Measures were collected prospectively for patients with acute agitation and schizophrenia (DSM IV diagnosis criteria) who consulted consecutively two ED: one in Belgium and the other one in Switzerland. Consent was obtained subsequently. A group of 40 patients with severe agitation and SCZ received olanzapine 10 mg IM. Efficacy and safety data (blood pressure, pulse, extrapyramidal symptoms) were assessed at baseline, two hours post-injection and at discharge., Results: Significant reductions of agitation associated with good tolerance were observed two hours after the first IM olanzapine (PANSS EC declined from 28.6 +/- 4.13 to 16.8 +/- 4.8). Only 5% of patients required a second IM olanzapine. The absence of clinically significant extrapyramidal and cardiovascular side effects is promising, but considering the statistically significant reduction of systolic and diastolic blood pressure and pulse, vital signs should be checked especially in the first 2 hours post injection., Conclusions: This naturalistic study suggest a promising efficacy and safety balance of intramuscular olanzapine in patients with acute agitation and schizophrenia in emergency.

Objective: To report efficacy and safety of transitioning patients receiving intramuscular (IM) formulations of aripiprazole or haloperidol to their respective oral formulations., Methods: 448 agitated patients with schizophrenia (73%) or schizoaffective disorder (27%) were randomized to receive aripiprazole IM 9.75 mg, haloperidol IM 6.5 mg, or placebo IM within 24 hours. Patients treated with aripiprazole IM or haloperidol IM who completed this 24-hour IM phase were transitioned to the respective blinded oral formulations for 4 days (aripiprazole 10-15 mg/day, n = 153; haloperidol 7.5-10 mg/day, n = 151). Patients treated with placebo IM were transitioned to oral aripiprazole (analysis not included). The primary efficacy measure was mean change in Positive and Negative Syndrome Scale-Excited Component (PEC) score from baseline of oral phase (last value from 24-hour IM phase) to endpoint (study day 5, last observation carried forward)., Results: During the oral phase, aripiprazole 15 mg and haloperidol 10 mg were both effective in maintaining responses achieved on all efficacy measures during the 24-hour IM phase. Mean improvements in PEC scores from study day 1 to 5 were -1.37 for aripiprazole and -1.40 for haloperidol (p = NS for aripiprazole versus haloperidol). Oral aripiprazole was well tolerated. Extrapyramidal symptom-related adverse events were lower for aripiprazole (1.3%) than haloperidol (8.0%). Nausea and vomiting occurred more frequently in patients receiving aripiprazole (3.9% and 2.6%, respectively) than in those receiving haloperidol (0.7% and 1.3%, respectively)., Conclusions: Acutely agitated patients with schizophrenia or schizoaffective disorder treated with aripiprazole IM or haloperidol IM demonstrated similar effective and safe transition to their respective oral formulations. Initial benefits of reduced agitation and improved clinical status during the IM phase of the study were maintained throughout the oral phase of the study with good tolerability.

Objective: Despite the frequency of borderline personality disorder (BPD) in patients with acute agitation in emergency departments (EDs), there are few data about the use of intramuscular (IM) psychotropics in those patients. This is the first open-label study with olanzapine in this setting., Method: Measures were collected prospectively for patients with acute agitation in ED. Consent was obtained subsequently and diagnosis ascertained using the Structured Clinical Interview for DSM-IV. A group of 25 patients with severe agitation and BPD received olanzapine 10 mg IM. Efficacy and safety data are available at baseline, 2 h postinjection and at discharge., Results: Significant reductions of agitation associated with good tolerance were observed 2 h after the first IM olanzapine. Sixteen percent of patients required a second IM olanzapine., Conclusions: Randomized, placebo-controlled studies are needed to confirm the efficacy of IM olanzapine in patients with acute agitation and BPD.

Introduction: Chemical restraint is controversial. Appropriate use is ill-defined and chemical restraint may be overutilized. During the period of an unrelated observational study for patients with acute psychomotor agitation in a psychiatric emergency service, we noticed a significant reduction in the number of involuntary intramuscular injections administered., Results: We observed a 27% decrease (P=.015) in the number of involuntary intramuscular injections in the 3-month observational study period, compared to 3-month periods before and after the study., Conclusion: We suggest that the observation process itself may have been beneficial and may have reduced the incidence of unnecessary intramuscular injections.

This retrospective study of patients treated in a ninety-day, inpatient, dual-diagnosis treatment program examined antipsychotic effectiveness in this population using length of stay in treatment and successful program completion as outcome measures. All patients with co-occurring substance dependence and schizophrenia or schizoaffective disorder treated with olanzapine, risperidone, ziprasidone, and typical depot neuroleptics from January 2001 to December 2003 (N = 55) are the subjects of this study. Patients stayed longer in treatment when taking risperidone (82 +/- 19 days) or ziprasidone (74 +/- 21 days) compared with olanzapine (44 +/- 30 days) or typicals (47 +/- 36 days). Eighty-eight percent of risperidone patients and 64% of ziprasidone patients successfully completed the program, while only 33% of olanzapine patients and 40% of patients on typicals successfully completed the program. Risperidone and ziprasidone were associated with significantly better program performance than olanzapine or depot typicals in this population. Possible reasons for this difference are discussed.

Acute agitation is a common psychiatric emergency often treated with intramuscular (i.m.) medication when rapid control is necessary or the patient refuses to take an oral agent. Conventional i.m. antipsychotics are associated with side effects, particularly movement disorders, that may alarm patients and render them unreceptive to taking these medications again. Ziprasidone (Geodon) is the first second-generation, or atypical, antipsychotic to become available in an i.m. formulation. Ziprasidone IM was approved by the Food and Drug Administration in 2002 for the treatment of agitation in patients with schizophrenia. In October 2004, a roundtable panel of physicians with extensive experience in the management of acutely agitated patients met to review the first 2 years of experience with this agent. This monograph, a product of that meeting, discusses clinical experience to date with ziprasidone IM and offers recommendations on its use in various settings. In clinical trials, patients treated with ziprasidone IM demonstrated significant and rapid (within 15-30 minutes) reduction in agitation and improvement in psychotic symptoms, agitation, and hostility to an extent greater than or equal to that attained with haloperidol i.m. Tolerability of ziprasidone IM was superior to that of haloperidol IM, with a lower burden of movement disorders. Clinical trials have also shown that ziprasidone IM can be administered with benzodiazepines without adverse consequences. Transition from i.m. to oral ziprasidone has been well tolerated, with maintenance of symptom control. The most common adverse events associated with ziprasidone IM were insomnia, headache, and dizziness in fixed-dose trials and insomnia and hypertension in flexible-dose trials. No consistent pattern of escalating incidence of adverse events with escalating ziprasidone doses has been observed. Changes in QTc interval associated with ziprasidone at peak serum concentrations are modest and comparable to those seen with haloperidol IM. Results of randomized clinical trials of ziprasidone IM have been corroborated in studies in real-world treatment settings involving patients with extreme agitation or a recent history of alcohol or substance abuse. In these circumstances, clinically significant improvement was seen within 30 minutes of ziprasidone IM administration, without regard to the suspected underlying etiology of agitation. Agents with a good safety/tolerability profile, such as ziprasidone IM, may be more cost effective long term than older agents, due to reduced incidence of acute adverse effects (eg, acute dystonia) that often require extended periods of observation. Additional trials of ziprasidone IM in agitated patients in a variety of clinical setting are warranted to generate comparative risk/benefit data with conventional agents and other second-generation antipsychotics.

Acute agitation is a therapeutic dilemma. Rapid control of agitation is necessary to minimize danger both to recipients of care and to caregivers. Although a comprehensive assessment may ultimately be necessary to determine the cause of agitation and to identify or exclude underlying medical illness, it is often imperative to treat agitation immediately. In this imperfect clinical world, it is essential to have treatments that are both safe and effective for patients with a wide variety of causes of agitation.

Psychiatric emergency services (PES) are an increasingly important component of mental health services. To assess the type and scope of services delivered in the PES setting, the American Association for Emergency Psychiatry sponsored an Expert Consensus Panel Survey of these services in 1999. The questionnaire was mailed to medical directors of PES facilities with 91% (n = 51) responding. More than 90% of the respondents were teaching sites. Restraints were reportedly used in a mean of 8.5% of presentations for a mean of 3.3 h per episode. Restraint utilization correlated with the percentage of psychotic patients treated, but not with a wide variety of other patient and service variables. Involuntary medications were used in 16% of cases, though in oral form in 29% of those cases. A large majority (94%) endorsed mild sedation permitting further assessment as the appropriate endpoint and rejected sleep or heavy sedation as an endpoint (82%). Benzodiazepines received the strongest endorsements and 82% indicated it would be appropriate to administer a benzodiazepine alone for agitation first and initiate antipsychotic treatment subsequently if appropriate. When there is no history of prior antipsychotic exposure, 60% favored a benzodiazepine alone. However, given a history of previous antipsychotic treatment, only 8% endorsed this strategy. Most respondents (78%) preferred to use oral medication for treating behavioral emergencies, whenever possible but 70.3% reported regular use of an IM combination of a benzodiazepine and high-potency typical neuroleptic when necessary. In addition to managing emergencies, 82% of services initiated standing medications for patients being admitted to hospital settings and 70% initiated regular medication treatments for patients being released to the community. Of patients started on oral antipsychotics, 42% received an atypical antipsychotic. Reflecting medication characteristics of particular importance in emergency settings, most respondents (92%) cited selective serotonin reuptake inhibitors as the preferred type of antidepressant, and divalproex or related compounds (90%) for treatment of bipolar disorder in the PES.

Agitation is a common and difficult problem in psychiatric patients; patients with bipolar disorder constitute a substantial proportion of the agitated psychiatric population. Agitation is often seen in bipolar patients during acute manic states, when increased energy levels and reduced need for sleep lead patients to collide with the limits of others. Agitation also occurs during mixed and depressive states, which are characterized by fluctuating energy levels and periods of irritability. Although the prevalence of agitation is similar in men and women, its presentation often differs between the sexes. In addition, the presentations of bipolar disorder in children and in geriatric patients, and thus the manifestations of illness-related agitation, differ both from each other and from that of younger adults. Intensive treatment is required to manage agitated bipolar patients in a manner that rapidly decreases their suffering and maintains their safety and the safety of those around them. Considerations of speed and predictability tend to drive decisions in this setting more than concerns about tolerability. Oral or parenteral benzodiazepines, alone or in combination with an antipsychotic, are recommended as first-line treatment for the termination of behavioral emergencies in mania. Once behavioral control is restored, evidence suggests the combination of orally loaded divalproex sodium with an atypical antipsychotic is associated with more rapid improvement. Medication treatment of children and of geriatric patients must take into account developmental influences on the presentation of bipolar disorder in these different patient groups.

Objectives: Behavioral emergencies are a common and serious problem for consumers, their communities, and the healthcare settings on which they rely to contain, assess, and ultimately help the individual in a behavioral crisis. Partly because of the inherent dangers of this situation, there is little research to guide provider responses to this challenge. Key constructs such as agitation have not been adequately operationalized so that the criteria defining a behavioral emergency are vague. The significant progress that has been made for some disease states with better treatments and higher consumer acceptance has not penetrated this area of practice. A significant number of deaths of patients in restraint has focused government and regulators on these issues, but a consensus about key elements in the management of behavioral emergencies has not yet been articulated by the provider community. The authors assembled a panel of 50 experts to define the following elements: the threshold for emergency interventions, the scope of assessment for varying levels of urgency and cooperation, guiding principles in selecting interventions, and appropriate physical and medication strategies at different levels of diagnostic confidence and for a variety of etiologies and complicating conditions., Method: In order to identify issues in this area on which there is consensus, a written survey with 808 decision points was developed. The survey was mailed to a panel of 52 experts, 50 of whom completed it. A modified version of the RAND Corporation 9-point scale for rating appropriateness of medical decisions was used to score options. Consensus on each option was defined as a non-random distribution of scores by chi-square "goodness-of-fit" test. We assigned a categorical rank (first line/preferred choice, second line/alternate choice, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean rating. Guideline tables were constructed describing the preferred strategies in key clinical situations., Results: The expert panel reached consensus on 83% of the options. The relative appropriateness of emergency interventions was ascertained for a continuum of behaviors. When asked about the frequency with which emergency interventions (parenteral medication, restraints, seclusion) were required in their services, 47% of the experts reported that such interventions were necessary for 1%-5% of patients seen in their services and 32% for 6%-20%. In general, the consensus of this panel lends support to many elements of recent Health Care Financing Administration regulations, including the timing of clinician assessment and reassessment and the intensity of nursing care. However, the panel did not endorse the concept of "chemical restraint," instead favoring the idea that medications are treatments for target behaviors in behavioral emergencies even when the causes of these behaviors are not well understood. Control of aggressive behavior emerged as the highest priority during the emergency; however, preserving the physician-patient relationship was rated a close second and became the top priority in the long term. Oral medications, particularly concentrates, were clearly preferred if it is possible to use them. Benzodiazepines alone were top rated in 6 of 12 situations. High-potency conventional antipsychotics used alone never received higher ratings than benzodiazepines used alone. A combination of a benzodiazepine and an antipsychotic was preferred for patients with suspected schizophrenia, mania, or psychotic depression. There was equal support for high-potency conventional or atypical antipsychotics (particularly liquids) in oral combinations with benzodiazepines. Droperidol emerged in fourth place in some situations requiring an injection., Conclusions: To evaluate many of the treatment options in this survey, the experts had to extrapolate beyond controlled data in comparing modalities with each other or in combination. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide some direction for addressing common clinical dilemmas in the management of psychiatric emergencies and can be used to inform clinicians in acute care settings regarding the relative merits of various strategies.

Under intense public pressure, regulatory agencies have recently defined circumstances in which medications will be considered a form of restraint, so-called "chemical restraint." This article proposes that the emergency management of the agitated patient be viewed as a brief departure from the usual physician-patient collaboration. Viewed in this way, the goal is simply to terminate the emergency in the manner most likely to be acceptable to patients and conducive to a more typical dialogue. To that end, the author reviews all controlled studies of medication treatment of agitation that have appeared in English since the advent of the neuroleptic medications. Issues of diagnosis, relative efficacy, dosage, route, onset, offset, safety, tolerability, and consumer preference are considered.

Antipsychotic dosing for acute mania has not been well studied. Combined treatment with lithium and an antipsychotic is the most common treatment, but additional antimanic efficacy of a lithium-antipsychotic combination beyond that of an antipsychotic alone has not been well demonstrated. Furthermore, the possibility that lithium could affect antipsychotic dose requirement is believed to have never been studied. In this study, 63 acutely psychotic bipolar manic inpatients were randomly assigned to receive double-blind treatment with 1 of 2 haloperidol doses, 25 mg/day or 5 mg/day, for 21 days. In addition to haloperidol, subjects were randomly assigned to receive concomitant treatment with placebo, standard lithium, or lorazepam 4 mg/day. The high haloperidol dose produced greater improvement and more side effects than did the low dose. Lithium added to the low dose produced a markedly greater clinical response than did the low dose alone. Lorazepam did not improve the outcome for the patients receiving low-dose haloperidol. The clinical response produced by high-dose haloperidol was not enhanced by adding either lithium or lorazepam. All treatment effects emerged by the fourth day of treatment and persisted. Used alone, a haloperidol dose of 5 mg/day is too low for most manic patients, but concomitant lithium produces a dose-dependent enhancement of haloperidol response. Lorazepam 4 mg/day was insufficient to produce an advantage when added to low-dose haloperidol.