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intervention as compared to other therapeutic options for the individual patient. The full text of the practice guideline includes a detailed description of expert consensus findings and research evidence related to effects of antipsychotic medication in individuals with dementia. It also describes aspects of guideline implementation that are relevant to individual patients’ circumstances and clinical presentation.

Effect sizes for drug interventions in dementia are disappointingly small compared with the changes that psychiatrists are accustomed to seeing when they treat depression or psychosis in their patients who do not have dementia. The lesson from trials of cholinesterase inhibitors and memantine—that these treatments offer improvements in cognition and function that are robustly statistically significant in clinical trials but cannot be reliably detected in an individual patient—also applies to treatments for the noncognitive symptoms and signs seen in people with dementia. Initial clinical optimism about efficacy of atypical antipsychotics in the management of a wide range of distressing and difficult-to-manage symptoms and behaviors has been dampened by the failure to demonstrate superiority over placebo (1) and by evidence of severe harms (2). Risperidone has a license in the European Union for short-term treatment of aggression in dementia, and clinicians make decisions abouttheuseofatypicalantipsychoticsinthissituationbased on the presence of psychotic symptoms or consideration of the levels of risk associated with behaviors in an individual patient (3). But the search for effective and safe drug treatmentsforpsychosis,depression,agitation,aggression, and apathy in dementia is very much ongoing. Given the complexity of the symptoms and behaviors and their individual etiology, involving patient-unique interactions between an impaired brain and an imperfect environment, it should come as no surprise when trials report only modest benefits that, when considered for the average participant in the study, would not be regarded as clinically important (4). Therefore, emphasis has turned to identifying what characterizes patients who do or do not respond to treatment. The article by Schneider and colleagues (5) in this issue reports univariate and two-stage multivariate subgroup analyses from the Citalopram for Agitation in Alzheimer’s Disease (CitAD) trial. These subgroup analyses were conducted to investigate heterogeneity of response among individual trial participants and to identify factors that would predict response to citalopram and placebo. Primary outcome results from the CitAD trial included a mean 0.93-point advantage for citalopram on the 18-point Neurobehavioral Rating Scale agitation subscale and 40% of citalopram participants and 26% of placebo participants showing a moderate or marked improvement from baseline on the Alzheimer Disease Cooperative Study–Clinical Global Impression of Change (6). Worsening of cognitive function andQTintervalprolongationwereseenwiththehighdosage of citalopram used (30 mg/day), and benefits were partly attributabletosedation(7).Forthepresentstudy,theauthors initially chose 11 individual potential predictors of treatment response(age,gender,residencestatus,presenceofpsychosis, functional and cognitive impairment, agitation severity, and use of memantine, lorazepam, trazodone, or a cholinesterase inhibitor within 3 weeks of baseline). Of these, only residence statushadasignificanteffect, sothat patientslivingathome or with relatives showed a significantly greater citalopram effect compared with placeb ot han patients in long-term care. A post hoc exploratory two-stage multivariate analysis involved five of the 11 baseline factors shown to be the best response predictors (age, residence status, cognitive impairment, agitation severity, and lorazepam use). These baseline covariate values were used to compute an index score for each participant, which was essentiallyapredictedprobability of response with citalopram or placebo treatment. When participants were divided into deciles depending on their index scores, a marked heterogeneity of treatment effect for citalopram compared with placebo across the study population became apparent; Figure 3 in the article is the clearest illustration of this. Essentially, participants in the ninth and 10th deciles (thosewhowereleastaffectedbydementiaandhadmoderate levels of agitation) showed very strong positive response effects for citalopram compared with placebo, and participants in the first decile showed very strong positive response effects for placebo compared with citalopram, while the remaining70%ofparticipantsshowedverylittleinthewayof response. Citalopram was most effective in the subgroup of participants who were outpatients, had mild cognitive impairment, had moderate to moderately severe agitation, and

The diagnosis of major depressive disorder consists of the core features of depressed mood and/or the loss of interest or pleasure. Yet, accompanying vegetative symptoms can be polar opposites, including insomnia or hypersomnia, psychomotor agitation or retardation, and increase or decrease in appetite. This variability in symptom presentation suggests that major depressive disorder is not a unitary disorder. From a neurobiological point of view, major depressive disorder symptoms appear likely to be caused by differential and reciprocal disruption of the interconnected networks of awareness, interoception, and reward, all of which have been implicated in emotional regulation. Insight into individual differences in dysfunction among regional “nodes” of these circuits might lead to greater insight regarding more tailored treatment of phenotypic subgroups of depression. The development of the Research Domain Criteria (RDoC) project supported by the National Institute of Mental Health is an example of this conceptual shift away from framing disorders by discrete categories to an understanding of symptom clusters basedonbrain-behavior relationships (https://www. nimh.nih.gov/research-priorities/rdoc/index.shtml). In this issue of the Journal, W. Kyle Simmons, Ph.D., et al. (1) investigate activity in brain regions associated with responsivity to food stimuli in major depressive disorder subjectswith increasedordecreasedappetite.Theauthorsuseda task-based functional MRI (fMRI) measure to compare their major depressive disorder subjects to a control group of nondepressed, healthy individuals (N516 per group). Most participants were women, and all had similar body mass index values. The main measure of brain activity was the bloodoxygen-level-dependent (BOLD) response when participants passively viewed pictures of food compared with nonfood. In the healthy comparison group, an interconnected network of brain areas associated with viewing food included regions within the visual cortex, bilateral insula, medial orbitofrontal and prefrontal cortices, and right amygdala. These regions have been implicated to underlie interoceptive processing (2). Many other studies also show that these regions have altered activity in depressed patients and emotional processing in healthy control subjects (3, 4). In the Simmons et al. study, different patterns of change emerged for major depressive disorder subjects with appetite increases versus decreases. Themajor depressive disorder group with increased appetite had increased BOLD response in brain regions implicated in the reward system (anterior insula, orbitofrontal cortex, ventral striatum, ventral pallidum,andputamen) (5),while the appetitedecrease group generally showed decreased mid-insula BOLD activity compared with the other groups. Simmons et al. suggest that this altered reactivity of the interoceptive system when confronted with food stimuli leads to a disconnect of signaling from the periphery of a need to eat and a typical response to being presented with food (e.g., the depressed subjectwith lowappetitemaynot “feel like”eatingandwillnot choose to eat even though she may have visceral changes that usually cue hunger). The authors also examine brain regional connectivity changes, comparing resting-state fMRI as a functionof participant foodpleasantness scores. Thisprovides more support for differential changes based on appetite condition in themajordepressivedisordergroups, usingmeasures that are not dependent on specificity of neural changes associated with task-based fMRI. They find regional connectivity results with similar relationships to their findings with the task-based BOLD response. The role of brain regions critical in interoceptive processing appears promising to lead to exciting discoveries for some major depressive disorder treatment. A key role for interoception is maintaining homeostasis. Conceptualizing depression as a disruption of maintenance of homeostasis is an important consideration for novel medications or targets for invasive and noninvasive treatments (3, 6–8). Indeed, this approach to depression has been considered in conceptualizing how cognitive-behavioral therapy and related therapies alleviate symptoms (9). The Simmons laboratory focuses on appetite and the insula rather than on the general category of major depressive disorder. In this study, they did not include a group of major depressive disorder individuals who do not show a change in appetite. Therefore, we cannot predict what an anhedonic major depressive disorder group of individuals who do not have appetite problemswould show on either the fMRI tasks or the food preference responses. However, having major depressive disorder appetite changes studied by those interested in homeostasis regulation and obesity may help the field approach these worrisome symptoms of depression from a different vantage point. Coupled with depression research, examining the reciprocal nature of these interconnected Having major depressive disorder appetite changes studied by those interested in homeostasis regulation and obesity may help the field approach these worrisome symptoms of depression from a different vantage point.

Pharmacological treatments for agitation and aggression in patients with Alzheimer's disease have shown limited efficacy. The authors assessed the heterogeneity of response to citalopram in the Citalopram for Agitation in Alzheimer Disease (CitAD) study to identify individuals who may be helped or harmed.In this double-blind parallel-group multicenter trial of 186 patients with Alzheimer's disease and clinically significant agitation, participants were randomly assigned to receive citalopram or placebo for 9 weeks, with the dosage titrated to 30 mg/day over the first 3 weeks. Five planned potential predictors of treatment outcome were assessed, along with six additional predictors. The authors then used a two-stage multivariate method to select the most likely predictors; grouped participants into 10 subgroups by their index scores; and estimated the citalopram treatment effect for each.Five covariates were likely predictors, and treatment effect was heterogeneous across the subgroups. Patients for whom citalopram was more effective were more likely to be outpatients, have the least cognitive impairment, have moderate agitation, and be within the middle age range (76-82 years). Patients for whom placebo was more effective were more likely to be in long-term care, have more severe cognitive impairment, have more severe agitation, and be treated with lorazepam.Considering several covariates together allowed the identification of responders. Those with moderate agitation and with lower levels of cognitive impairment were more likely to benefit from citalopram, and those with more severe agitation and greater cognitive impairment were at greater risk for adverse responses. Considering the dosages used and the association of citalopram with cardiac QT prolongation, use of this agent to treat agitation may be limited to a subgroup of people with dementia.

This study evaluated the impact of antipsychotic review, social interaction, and exercise, in conjunction with person-centered care, on antipsychotic use, agitation, and depression in people with dementia living in nursing homes.A cluster-randomized factorial controlled trial with two replications was conducted in people with dementia in 16 U.K. nursing homes. All homes received training in person-centered care. Eight homes were randomly assigned to antipsychotic review, to a social interaction intervention, and to an exercise intervention for 9 months, with most homes assigned to more than one intervention. The primary outcome measures were antipsychotic use, agitation, and depression. Secondary outcome measures were overall neuropsychiatric symptoms and mortality.Antipsychotic review significantly reduced antipsychotic use by 50% (odds ratio 0.17, 95% confidence interval [CI] 0.05 to 0.60). Antipsychotic review plus the social interaction intervention significantly reduced mortality (odds ratio 0.26, 95% CI 0.13 to 0.51) compared with the group receiving neither. The group receiving antipsychotic review but not the social intervention showed significantly worse outcome in neuropsychiatric symptoms compared with the group receiving neither (score difference +7.37, 95% CI 1.53 to 13.22). This detrimental impact was mitigated by concurrent delivery of the social intervention (-0.44, CI -4.39 to 3.52). The exercise intervention significantly improved neuropsychiatric symptoms (-3.59, 95% CI -7.08 to -0.09) but not depression (-1.21, CI -4.35 to 1.93). None of the interventions had a significant impact specifically on agitation.While reductions in antipsychotic use can be achieved by using a "real world" intervention, this may not be of benefit to people with dementia in the current climate of more judicious prescribing unless nonpharmacological interventions such as social interaction or exercise are provided in parallel.

“Ms. M,” a 65-year-old Caucasian woman with end-stage chronic obstructive pulmonary disease related to smoking and a-1-antitrypsin MS phenotype, developed an abrupt onset of agitation and confusion and was admitted to the medical service of a local hospital. Until then, her only psychiatric treatment was for anxiety, which had been treated with escitalopram for the previous 5 months. Shortly after a dosage adjustment for increased anxiety symptoms (from 10 mg/day to 20 mg/day), Ms. M became acutely restless, anxious, and cognitively disorganized. She was found to be hypercarbic but not hypoxic on her normal dosage of supplemental oxygen (see Table 1 for details). The patient’s medications on admission included escitalopram, prednisone, esomeprazole, diltiazem, tiotropium, and fluticasone. EEG showed mild diffuse slowing. A serum sodium level of 126 mEq/L (reference range, 135–145 mEq/L) suggested escitalopram-associated syndrome of inappropriate secretion of antidiuretic hormone, so the drug was discontinued, the hyponatremia was corrected, and the patient was discharged in 4 days, much improved. Her prednisone dosage was unchanged. Five days later, Ms. M exhibited unusually intense cleaning behavior at home, pressured speech, flight of ideas, and paranoid delusions. She was returned to the emergency department, from which she immediately fled, attempting to run into traffic before being coaxed back inside. She was sedated with intramuscular injections of haloperidol and lorazepam and admitted to the medicine department (admission 2 in Table 1). Her electrolyte levels were normal and her blood gases essentially unchanged. The consulting psychiatrist noted the patient’s anxiety and compulsive behavior and prescribed sertraline, buspirone, and alprazolam. Ms. M’s pulmonologist tapered her prednisone dosage by 25%. Ms. M calmed without further incident and was discharged 3 days later. Within 2 weeks, she again rapidly decompensated; she was observed to be speaking feverishly on the telephone without anyone on the other end, and she stayed awake at night, writing nonsensically. She began to insist falsely that her husband was a verbally abusive alcoholic and became irate when challenged. On admission to a local psychiatric unit (admission 3), she was noted to have elated mood, pressured speech, flight of ideas, decreased need for sleep (3 hours nightly), delusions, and psychomotor agitation. Sertraline was discontinued (as a possible cause of her manic symptoms), olanzapine was introduced, and lithium was added without significant benefit. Results from a battery of tests, including lumbar puncture, heavy metal screen, HIV, antinuclear antibodies, Lyme disease, rapid plasma reagin, erythrocyte sedimentation rate, and levels of ceruloplasmin, C-reactive protein, and B12, were all normal. EEG showed slow waves, but was read as “normal.” A brain MRI revealed no interval change. The psychiatric treatment team, noting the “normal” EEG and continuing mood lability, agitation, and paranoia, recommended ECT for presumed psychotic mania. Examinations several times during the hospitalization found Ms. M to have been oriented, although memory impairment was noted on admission and again on the day before initiation of ECT, when her attending psychiatrist documented impairment in concentration as well as in remote and recent memory. Ms. M then received three bifrontal ECT treatments, with fleeting improvement of agitation but no return to baseline. She was discharged home with 24-hour private-duty nursing support. Her medication regimen included olanzapine, alprazolam, and a reduced dosage of prednisone. She was removed from the lung transplant waiting list because of her psychiatric admission. Three additional outpatient bifrontal ECT treatments, a retrial of lithium (serum level, 0.5 mmol/L), and continued olanzapine failed to stem worsening disorganization. Two months after the first appearance of agitation and confusion, Ms. M traveled out of state to be admitted to the mood disorders unit at Johns Hopkins Hospital (admission 4). On arrival, she had an unsteady gait and was minimally cooperative. She grabbed at random objects, attempted to remove her clothing, and attempted to get into the shower while dressed. Her speech was slow, dysarthric, and tangential. Her mood alternated between irritable and cheerful. She accused her husband of being an alcoholic. She was oriented only to person, scoring 17 (out of 30) on the Mini-Mental State Examination (MMSE). Her medications on admission included olanzapine, prednisone, alprazolam as needed, diltiazem, omeprazole, fluticasone, and ipratropium. EEG revealed bilateral posterior slowing. Blood gas levels indicated well-compensated chronic hypercarbia (PaCO2 now up to 70 mmHg). The patient’s lithium level was not assessed, as lithium had been discontinued several days before admission. An extensive delirium workup for serum markers of metabolic, nutritional, autoimmune, endocrine

The prion diseases are rare neurodegenerative conditions that cause complex and highly variable neuropsychiatric syndromes, often with remarkably rapid progression. Prominent behavioral and psychiatric symptoms have been recognized since these diseases were first described. While research on such symptoms in common dementias has led to major changes in the way these symptoms are managed, evidence to guide the care of patients with prion disease is scarce. The authors review the published research and draw on more than 10 years' experience at the U.K. National Prion Clinic, including two large prospective clinical research studies in which more than 300 patients with prion disease have been followed up from diagnosis to death, with detailed observational data gathered on symptomatology and symptomatic treatments. The authors group behavioral and psychiatric symptoms into psychotic features, agitated features, and mood disorder and describe their natural history, showing that they spontaneously improve or resolve in many patients and are short-lived in many others because of rapid progression of global neurological disability. Diagnostic category, disease severity, age, gender, and genetic variation are or may be predictive factors. The authors review the observational data on pharmacological treatment of these symptoms in the U.K. clinical studies and make cautious recommendations for clinical practice. While nonpharmacological measures should be the first-line interventions for these symptoms, the authors conclude that there is a role for judicious use of pharmacological agents in some patients: antipsychotics for severe psychosis or agitation; benzodiazepines, particularly in the late stages of disease; and antidepressants for mood disorder.

The authors sought to determine the effects of conventional and atypical antipsychotic use on time to nursing home admission and time to death in a group of outpatients with mild to moderate probable Alzheimer's disease.The authors examined time to nursing home admission and time to death in 957 patients with the diagnosis of probable Alzheimer's disease who had at least one follow-up evaluation (mean follow-up time, 4.3 years [SD=2.7]; range, 0.78-18.0 years) using Cox proportional hazard models adjusted for age, gender, education level, dementia severity, hypertension, diabetes mellitus, heart disease, extrapyramidal signs, depression, psychosis, aggression, agitation, and dementia medication use.A total of 241 patients (25%) were exposed to antipsychotics at some time during follow-up (conventional, N=138; atypical, N=95; both, N=8). Nursing home admission (63% compared with 23%) and death (69% compared with 34%) were more frequent in individuals taking conventional than atypical antipsychotics. In a model that included demographic and cognitive variables, hypertension, diabetes mellitus, heart disease, incident strokes, and extrapyramidal signs, only conventional antipsychotic use was associated with time to nursing home admission. However, the association was no longer significant after adjustment for psychiatric symptoms. Psychosis was strongly associated with nursing home admission and time to death, but neither conventional nor atypical antipsychotics were associated with time to death.The use of antipsychotic medications, both conventional and atypical, was not associated with either time to nursing home admission or time to death after adjustment for relevant covariates. Rather, it was the presence of psychiatric symptoms, including psychosis and agitation, that was linked to increased risk of institutionalization and death after adjustment for exposure to antipsychotics.

The study measured the effects of atypical antipsychotics on psychiatric and behavioral symptoms in patients with Alzheimer's disease and psychosis or agitated behavior.The Clinical Antipsychotic Trials of Intervention Effectiveness-Alzheimer's Disease (CATIE-AD) Alzheimer's disease effectiveness study included 421 outpatients with Alzheimer's disease and psychosis or agitated/aggressive behavior. Patients were assigned randomly to masked, flexible-dose treatment with olanzapine, quetiapine, risperidone, or placebo for up to 36 weeks. Patients could be randomly reassigned to a different medication at the clinician's discretion, which ended phase 1. Psychiatric and behavioral symptoms, functioning, cognition, care needs, and quality of life were measured at regular intervals.In relation to placebo, the last observation in phase 1 showed greater improvement with olanzapine or risperidone on the Neuropsychiatric Inventory total score, risperidone on the Clinical Global Impression of Changes, olanzapine and risperidone on the Brief Psychiatric Rating Scale (BPRS) hostile suspiciousness factor, and risperidone on the BPRS psychosis factor. There was worsening with olanzapine on the BPRS withdrawn depression factor. Among patients continuing phase 1 treatment at 12 weeks, there were no significant differences between antipsychotics and placebo on cognition, functioning, care needs, or quality of life, except for worsened functioning with olanzapine compared to placebo.In this descriptive analysis of outpatients with Alzheimer's disease in usual care settings, some clinical symptoms improved with atypical antipsychotics. Antipsychotics may be more effective for particular symptoms, such as anger, aggression, and paranoid ideas. They do not appear to improve functioning, care needs, or quality of life.

Mr. B is a 34-year-old man with a 13-year history of schizophrenia. His early treatment consisted of brief trials of first-generation antipsychotics, which he refused to take for any significant period of time. He was then started on risperidone at an average of 5 mg/day. Within a few months, he and his mother noticed that he had upper and lower extremity tremor and profound motor restlessness, especially of the legs. These symptoms worsened until Mr. B was taken off risperidone and started on olanzapine, after which the tremor resolved, but the restlessness persisted. Mr. B’s discomfort was so severe that he was unable to sit through a 15-minute medication management appointment without getting up and pacing the room. His mother noted that the restlessness lasted throughout the day, relenting only when he slept. Mr. B stated that he could not stay still for more than a few minutes at a time and that he had an irresistible urge to move, which led him to pace the house and neighborhood until the soles of his feet were bleeding. Mr. B’s mother also reported that when the restlessness was at its worst, he was extremely irritable, easily agitated, and sometimes violent.

OBJECTIVE:The study aimed to explore how prevalent agitated depression is in bipolar I disorder, whether it represents a mixed state, and whether it differs from nonagitated depression with respect to course and outcome. METHOD:From 313 bipolar I patients with an index episode of major depression, the authors selected those fulfilling Research Diagnostic Criteria for agitated depression. These 61 patients were compared to 61 randomly recruited bipolar I patients with an index episode of nonagitated depression and 61 randomly recruited bipolar I patients with an index episode of mania regarding demographic, historical, and clinical features. The two depressive groups were also compared regarding time to recovery from the index episode, treatment received for that episode, percentage of time spent in an affective episode during a prospective observation period, and 5-year outcome. RESULTS:Patients with agitated depression were consistently not elated or grandiose, but one-fourth had the cluster of symptoms with racing thoughts, pressured speech, and increased motor activity, and one-fourth had the paranoia-aggression-irritability cluster. Compared to patients with nonagitated depression, they had a longer time to 50% probability of recovery from the index episode, were more likely to receive standard antipsychotic drugs during that episode, and spent more time in an affective episode during the observation period. CONCLUSIONS:The occurrence of agitated depression in bipolar I disorder is not rare and has significant prognostic and therapeutic implications. Whether the co-occurrence of a major depressive syndrome with one or two of these symptomatic clusters makes up a "mixed state" remains unclear.

Objective: The goal of this study was to determine changes of circadian rhythms induced by Alzheimer’s disease and to explore relationships among rhythm disturbances, sundowning, and sleep disturbances in patients with Alzheimer’s disease. “Sundowning” is the occurrence or exacerbation of behavioral symptoms of Alzheimer’s disease in the afternoon and evening. Method: Circadian rhythms of core body temperature and motor activity were measured in 25 patients with diagnoses of probable Alzheimer’s disease and in nine healthy individuals. The subjects with Alzheimer’s disease were divided according to the occurrence of sundowning as determined by staff reports. Results: The subjects with Alzheimer’s disease had less diurnal motor activity, a higher percentage of nocturnal activity, lower interdaily stability of motor activity, and a later activity acrophase (time of peak) than did the healthy individuals. They also had a higher mesor (fitted mean) temperature, higher amplitude of the fitted cosine temperature curve, and later temperature acrophase than did the healthy subjects. The severity of sundowning was associated with later acrophase of temperature, less correlation of circadian temperature rhythm with a 24-hour cycle, and lower amplitude of temperature curve. Conclusions: These data indicate that Alzheimer’s disease causes disturbances of circadian rhythms and that sundowning is related to a phase delay of body temperature caused by Alzheimer’s disease.

The goal of this study was to compare the efficacy and side effects of two doses of haloperidol and placebo in the treatment of psychosis and disruptive behaviors in patients with Alzheimer's disease.In a 6-week random-assignment, double-blind, placebo-controlled trial (phase A), haloperidol, 2-3 mg/day (standard dose), and haloperidol, 0.50-0.75 mg/day (low dose), were compared in 71 outpatients with Alzheimer's disease. For the subsequent 6-week double-blind crossover phase (phase B), patients taking standard- or low-dose haloperidol were switched to placebo, and patients taking placebo were randomly assigned to standard- or low-dose haloperidol.For the 60 patients who completed phase A, standard-dose haloperidol was efficacious and superior to both low-dose haloperidol and placebo for scores on the Brief Psychiatric Rating Scale psychosis factor and on psychomotor agitation. Response rates according to three sets of criteria were greater with the standard dose (55%-60%) than the low dose (25%-35%) and placebo (25%-30%). The advantage of standard dose over low dose was replicated in phase B. In phase A, extrapyramidal signs tended to be greater with the standard dose than in the other two conditions, primarily because of a subgroup (20%) who developed moderate to severe signs. Low-dose haloperidol did not differ from placebo on any measure of efficacy or side effects.The results indicated a favorable therapeutic profile for haloperidol in doses of 2-3 mg/day, although a subgroup developed moderate to severe extrapyramidal signs. A starting dose of 1 mg/day with gradual, upward dose titration is recommended. The narrow therapeutic window observed with haloperidol may also apply to other neuroleptics used in Alzheimer's disease patients with psychosis and disruptive behaviors.

Objective The author reviewed the literature published since 1972 concerning restraint and seclusion. Method The review began with a computerized literature search. Further sources were located through citations from articles identified in the original search. Results The author synthesized the contents of the articles reviewed using the categories of indications and contraindications; rates of seclusion and restraint as well as demographic, clinical, and environmental factors that affect these rates; effects on patients and staff; implementation; and training. Conclusions The literature on restraint and seclusion supports the following. 1) Seclusion and restraint are basically efficacious in preventing injury and reducing agitation. 2) It is nearly impossible to operate a program for severely symptomatic individuals without some form of seclusion or physical or mechanical restraint. 3) Restraint and seclusion have deleterious physical and psychological effects on patients and staff, and the psychiatric consumer/survivor movement has emphasized these effects. 4) Demographic and clinical factors have limited influence on rates of restraint and seclusion. 5) Local nonclinical factors, such as cultural biases, staff role perceptions, and the attitude of the hospital administration, have a greater influence on rates of restraint and seclusion. 6) Training in prediction and prevention of violence, in self-defense, and in implementation of restraint and/or seclusion is valuable in reducing rates and untoward effects. 7) Studies comparing well-defined training programs have potential usefulness.

OBJECTIVE: Antidepressants have been associated with the induction of mania and rapid cycling. This study examined whether antidepressant-associated manic states differ in any way from spontaneous mania. METHOD: Forty-nine consecutive inpatients with antidepressant-associated manic states were compared with 49 matched inpatients with spontaneous mania in a blind, retrospective chart review. RESULTS: Across virtually every clinical measure examined, the patients with antidepressant-associated manic states experienced milder and more time-limited manic episodes than the patients with spontaneous mania. The patients with antidepressant-associated manic states were subject to frequent checking by nurses and hall restriction for a significantly shorter period of time than the patients with spontaneous mania. The patients with antidepressant-associated manic states also had significantly less severe levels of delusions, hallucinations, psychomotor agitation, and bizarre behavior, according to a standard rating instrument, than the patients with spontaneous mania. For further study the patients with antidepressant-associated mania were divided into subgroups taking four individual classes of antidepressant drugs: tricyclics (N = 19), fluoxetine (N = 13), monoamine oxidase inhibitors (MAOIs) (N = 8), and bupropion (N = 6); three patients taking combinations of drugs were not included in these analyses. The patients with MAOI- and bupropion-associated mania had a slightly lower overall rating of severity of psychopathology at admission than the subgroups with fluoxetine- and tricyclic-associated mania. CONCLUSIONS: Antidepressant-associated mania appears to be a milder and more time-limited syndrome than spontaneous mania and may represent a distinct clinical entity. MAOIs and bupropion may be associated with milder manic states than either tricyclic drugs or fluoxetine. Language: en

The authors explored differences in the clinical characteristics of 17 male and 13 female patients experiencing their first admission for psychotic depression. Few differences were observed for most depressive and psychotic features, but fewer male than female patients reported fatigue, psychomotor agitation, and systematized and mood-incongruent delusions and more male patients reported feelings of worthlessness. Overall, the findings were consistent with those derived from samples of patients with chronic, nonpsychotic mental illness.

Objective The authors' goal was to study the relationship between smoking status and clinical characteristics in schizophrenic patients. Method Seventy-eight schizophrenic outpatients were assessed by a single rater using the Brief Psychiatric Rating Scale (BPRS), the Abnormal Involuntary Movement Scale, and the Simpson-Angus Scale for extrapyramidal symptoms. Current smokers (N = 58) were compared with nonsmokers (N = 20) on clinical variables by independent t tests and chi-square tests. Differences in outcome variables were tested by multiple analysis of covariance (ANCOVA) with smoking status and gender as factors and age, neuroleptic dose, and caffeine consumption as covariates. Results Seventy-four percent of patients were current smokers and reported a mean of 19 cigarettes smoked per day. Compared to nonsmokers, current smokers were significantly more likely to be men, to be younger, and to have had an earlier age at onset and a greater number of previous hospitalizations. Current smokers and nonsmokers received mean neuroleptic doses of 1160 and 542 mg/day (chlorpromazine equivalents); the difference was significant. Current smokers also displayed significantly less parkinsonism and more akathisia and had higher total scores on the BPRS. Overall multiple ANCOVA demonstrated a significant main effect for smoking status but not gender or the interaction between gender and smoking status. Univariate ANCOVAs demonstrated a significant main effect of smoking status only for the Simpson-Angus Scale score. Conclusions Cigarette smokers receive significantly higher neuroleptic doses, in part because of a smoking-induced increase in neuroleptic metabolism. Smoking is also associated with significant reduction in levels of parkinsonism. Smoking status is a significant factor that should be considered in assessment of neuroleptic dose requirements and neuroleptic side effects.

Objective The authors tested the hypothesis that evening bright light pulses would improve sleep-wake patterns and reduce agitation in patients with Alzheimer's disease who have severe sundowning (a syndrome of recurring confusion and increased agitation in the late afternoon or early evening) and sleep disorders. Method Ten inpatients with Alzheimer's disease on a research ward of a veterans' hospital were studied in an open clinical trial. All patients had sundowning behavior and sleep disturbances. After a week of baseline measurements, patients received 2 hours/day of exposure to bright light between 7:00 p.m. and 9:00 p.m. for 1 week. During the baseline week, the treatment week, and a posttreatment week, patients were rated by nurses for agitation, sleep-wake patterns, use of restraints, and use of prescribed-as-needed medication. On the last 2 days of each week, patients wore activity monitors. Activity counts were analyzed for circadian rhythmicity. Results Clinical ratings of sleep-wakefulness on the evening nursing shift improved with light treatment in eight of the 10 patients. The proportion of total daily activity occurring during the nighttime decreased during the light-treatment week. The relative amplitude of the circadian locomotor activity rhythm, a measure of its stability, increased during the light-treatment week. More severe sundowning at baseline predicted greater clinical improvement. Conclusions Evening bright light pulses may ameliorate sleep-wake cycle disturbances in some patients with Alzheimer's disease. This effect may be mediated through a chronobiological mechanism.

OBJECTIVE: Beta-blocking agents, particularly propranolol, are considered effective in the treatment of neuroleptic-induced akathisia, but considerable controversy exists about the involved receptor subtype(s). The authors conducted a randomized, controlled trial comparing the effects of propranolol and betaxolol to determine whether central beta 1-adrenoceptor blockade is sufficient to correct neuroleptic-induced akathisia. METHOD: The subjects were 19 patients whose neuroleptic-induced akathisia responded to 20 mg/day of propranolol and subsequently reemerged during a placebo washout period. They were randomly assigned to propranolol (20 or 40 mg/day) or betaxolol (10 or 20 mg/day) and, after another placebo period, were switched to the second beta blocker. RESULTS: There was no significant difference in the antiakathisia effects of propranolol and betaxolol. CONCLUSIONS: The lack of difference between propranolol and betaxolol suggests that beta 1-adrenoceptor blockade is sufficient to improve neuroleptic-induced akathisia. The results of this explanatory study need therapeutic confirmation.

Objective The authors' goal was to determine the prevalence of and risk factors for neuroleptic-induced movement disorders in a group of psychiatrically hospitalized children and adolescents. Method They evaluated the presence or absence of parkinsonism, tardive dyskinesia, and akathisia in 104 children and adolescents who were in residence in or admitted over a 6-month period to a state-operated child psychiatric center. They applied a standardized, structured assessment procedure used in research on adult and geriatric psychiatric patients and the mentally retarded. Results The prevalence of parkinsonism among the 61 subjects at risk was 34% and was significantly associated with longer neuroleptic treatment periods immediately before evaluation. The prevalence of treatment-emergent tardive dyskinesia among the 41 subjects at risk was 12% and showed no association with quantitative neuroleptic treatment variables. However, patients with tardive dyskinesia were significantly more likely to have a family history of mental illness and significantly less likely to have a history of assaultive behavior. A pattern of complex pharmacological responses for parkinsonism and tardive dyskinesia, some of which are not typical of those most commonly reported in adults, was seen in this group of young patients. Conclusions The study data highlight the acute sensitivity of the neuroleptic-treated child and adolescent to the development of parkinsonism, the possible role of certain patient characteristics in the vulnerability to develop tardive dyskinesia, and the possibility that neuroleptic-induced side effects experienced by children and adolescents differ in some ways from those experienced by adults. The data further strongly support the need for systematic monitoring of neuroleptic-treated child and adolescent patients for a full range of side effects.

Fifty-nine elderly residents of long-term care facilities who had DSM-III diagnoses of dementia were studied in an 8-week randomized, double-blind comparison trial of haloperidol, oxazepam, and diphenhydramine to test the efficacy of these agents in the treatment of clinically significant behavioral disturbances in patients with dementia. All three agents demonstrated modest but significant efficacy as measured by clinician ratings of agitated behavior and activities of daily living. The absolute magnitude of improvement was greater for haloperidol and diphenhydramine than for oxazepam, but differences among groups did not approach statistical significance. Frequencies of acute adverse events during the trial were similar across the drug treatment groups. Although these drugs may differ in terms of long-term safety and efficacy, they appear to be equivalent for short-term management of agitated behavior in severely demented patients.

Ten male and 10 female nonalcoholic college students were given drinks having alcohol levels of 0, 0.5, 0.8, and 1.2 g/kg. They were then given four complex psychomotor tests, immediately before and after which they were given the Spielberger State Anxiety Inventory, and asked to rate their performance on a five-point scale. Mean anxiety change scores were -.90,.75, 4.75, and 5.55 for the four alcohol doses, respectively. There was no significant correlation between anxiety change and actual performance on the visual vigilance task, but for males there was a significant correlation between anxiety change and perceived level of impairment. Language: en

The symptoms of three bipolar patients remitted after clonidine treatment. One patient presented with mixed bipolar disorder, two were manic, and all were psychotic. One patient's akathisia also appeared to respond to clonidine. Clonidine's thymoleptic effect paralleled resulting cardiovascular changes.

Fourteen patients with neuroleptic-induced akathisia were treated with propranolol in an open trial. All patients demonstrated substantial improvement of their akathisia; nine of the 14 obtained complete remission. Response was quite rapid, occurring within 24 hours in most cases. Doses required for improvement were low (30-80 mg/day), and side effects were few. Lithium-induced tremor improved considerably, but symptoms of parkinsonism and tardive dyskinesia showed little change. Preliminary results with certain other beta blockers suggest that they are less effective than propranolol in the treatment of akathisia.

Intense exercise for one hour induced a significant increase in plasma cyclic adenosine monophosphate (cAMP) in 5 healthy volunteers. In 44 manic-depressive patients, cAMP levels correlated more strongly with mood ratings than with activity scores. The authors conclude that physical activity is one of the factors which contribute to changes of cAMP levels in affective illness.

The regional cerebral blood flow of 12 patients with severe alcohol withdrawal reactions (delirium tremens or impending delirium tremens) was measured during the acute state before treatment and after recovery. Greater cerebral blood flow was significantly correlated with visual hallucinations and agitation during the acute withdrawal reaction. The results suggest that delirium tremens and related clinical states represent a type of acute brain syndrome mainly characterized by CNS hyperexcitability.

The subjective response to antipsychotic medication was systematically evaluated in two samples of schizophrenic patients, one treated with haloperidol, the other with thiothixene. For both groups, a dysphoric response to the first dose was found to be a powerful predictor of noncompliance. A persisting dysphoric response was associated with a poor clinical outcome. Dysphoric responses were powerfully associated with akathisia. Patients' subjective responses were consistent throughout therapy, and there was moderate agreement between the patients' evaluation of the medication and the staff's ratings of improvement. The authors suggest that the subjective response to antipsychotic medication should not be dismissed and that dysphoric responses should be acknowledged.

The corrugator muscle region of the forehead has special significance in producing facial expressions associated with depression. Darwin observed in 1872 that contractions in the corrugator region produce peculiarly formed wrinkles on the forehead, referred to as "Omega Melancholium." In the present study, results from 61 right-handed, drug-free women with major depressive disorder showed a significant positive correlation between facial corrugator EMG values and psychomotor agitation. Results were not due to differences in severity of depression. These data offer preliminary evidence that agitation is reflected in corrugator muscle activity and may explain the "Omega sign" of melancholia.

The authors report two cases of impulsive suicide attempts associated with akathisia. In both cases, suicidal ideation appeared suddenly, concurrent with neuroleptic-induced akathisia, and disappeared when the akathisia was treated.

Six hospitalized patients with neuroleptic-induced akathisia were treated with clonidine under single-blind conditions. Akathisia and anxiety at maximum clonidine dose were significantly lower than at baseline, although it was difficult to differentiate specific therapeutic effects from sedation.

Extrapyramidal side effects are a major limitation in the use of neuroleptics, and tardive dyskinesia is a special public health problem. Accurate clinical diagnosis of extrapyramidal syndromes is necessary for effective management. The authors compared clinicians' recognition of the major extrapyramidal syndromes in 48 psychotic inpatients with independent blind diagnoses by clinical researchers using standardized ratings. The major finding was a high rate of clinical underrecognition of all major extrapyramidal syndromes, especially tardive dyskinesia. The authors discuss the clinical predictors of nonrecognition of extrapyramidal side effects and recommend improved training in their detection.