Response and remission rates with adjunctive aripiprazole in patients with major depressive disorder who exhibit minimal or no improvement on antidepressant monotherapy.

BACKGROUND: The efficacy of adjunctive aripiprazole in patients with major depressive disorder (MDD) with no improvement after 8 weeks of prior antidepressant monotherapy has not been evaluated. METHODS: A post hoc analysis of three similarly designed, randomised, double-blind, placebo-controlled, phase III studies was conducted investigating the efficacy and safety of aripiprazole adjunctive to standard antidepressant treatment (ADT) in MDD patients with a prior inadequate response to one to three ADTs. Minimal improvement to antidepressant monotherapy was defined as a Clinical Global Impressions - Improvement (CGI-I) score of 3 and non-improvement as a CGI-I of 4 at weeks 6 and 8 of antidepressant monotherapy. RESULTS: The end-point response rate for ADT minimal improvers receiving adjunctive aripiprazole was 38.8% vs. 26.6% for adjunctive placebo (p < 0.05; number needed to treat [NNT] = 9 [95% confidence interval: 4.8-27.7]), and for ADT non-improvers receiving adjunctive aripiprazole was 24.0% vs. 10.3% for adjunctive placebo (p < 0.05; NNT = 8 [95% confidence interval: 4.4-21.5]). ADT minimal improvers and non-improvers demonstrated significant improvements in response vs. ADT alone as early as after 1 and 2 weeks of adjunctive treatment, respectively. The end-point remission rate for ADT minimal improvers receiving adjunctive aripiprazole was 34.2% vs. 21.0% for adjunctive placebo (p < 0.05; NNT = 8), and for ADT non-improvers receiving adjunctive aripiprazole was 16.0% vs. 5.9% for adjunctive placebo (p < 0.05; NNT = 10). The most common adverse events for ADT minimal improvers and non-improvers receiving adjunctive aripiprazole were akathisia, restlessness and insomnia. CONCLUSION: Patients with minimal or no improvement after 8 weeks of antidepressant monotherapy significantly benefited from adjunctive aripiprazole treatment, supporting the efficacy of this treatment for MDD patients with all levels of response to ADT.

Antipsychotic drugs dose-dependently suppress the spontaneous hyperactivity of the chakragati mouse.

The chakragati (ckr) mouse has been proposed as a model of aspects of schizophrenia. The mice, created serendipitously as a result of a transgenic insertional mutation, exhibit spontaneous circling, hyperactivity, hypertone of the dopamine system, reduced social interactions, enlarged lateral ventricles, deficits in pre-pulse inhibition of acoustic startle and deficits in latent inhibition of conditioned learning. In this study, the dose-dependent effects of antipsychotic drugs (haloperidol, pimozide, risperidone, clozapine, olanzapine, ziprasidone, quetiapine and aripiprazole) on the spontaneous hyperactivity of the mice were investigated. All the antipsychotic drugs tested dose-dependently suppressed spontaneous hyperactivity. Aripriprazole, which is known to be a dopamine D2 receptor partial agonist, exhibited a tri-phasic dose-response, initially suppressing hyperactivity at low doses, having little effect on hyperactivity at intermediate doses, and suppressing activity again at high doses. These data suggest that the spontaneous circling and hyperactivity of the ckr mouse may allow screening of candidate antipsychotic compounds, distinguishing compounds with aripriprazole-like profiles.

Antipsychotic drug-induced weight gain: development of an animal model.

OBJECTIVE: Weight gain is a prominent effect of most atypical antipsychotic drugs (AAPDs); yet, the mechanisms are not fully understood and no well-established mouse models exist for investigating the mechanisms. Thus, we developed a mouse model to evaluate the effects of AAPDs on eating, body weight (BW), and body composition. METHODS: Female C57BL/6J mice were used to test olanzapine, quetiapine, ziprasidone, and risperidone. Mice were acclimated to individual housing, given ad libitum access to chow and water, dosed with placebo peanut butter pills for 1 week, and then dosed daily with AAPD-laced peanut butter pills for 4 weeks. Weekly food intakes and BWs were measured, and body compositions were determined at the end of each experiment. RESULTS: After 4 weeks of treatment, olanzapine, quetiapine, ziprasidone, and risperidone caused significant weight increases, but only olanzapine and quetiapine were associated with significantly increased food intake. Body composition data revealed that olanzapine-treated mice had more relative fat mass and risperidone-treated mice had more relative lean mass than did control mice. Quetiapine and ziprasidone did not significantly affect relative body composition even though BW was increased. CONCLUSIONS: Oral AAPD administration causes increased BW in female mice. Our mouse model of AAPD-induced weight gain resembles the human response to these medications and will be used to investigate the mechanisms for weight gain and fat accumulation.

The behavioral effects of acute and chronic JL 13, a putative antipsychotic, in Cebus non-human primates.

RATIONALE: Neuroleptic or antipsychotic drugs are the mainstay of treating acute and chronic psychosis. However, their efficacy is offset by a wide array of side effects, especially extrapyramidal syndromes (EPS). In an attempt to develop novel antipsychotic agents, several animal models have been developed to characterize the profile of new chemical entities. OBJECTIVE: To evaluate the behavioral characteristics of JL 13, a potentially unique antipsychotic agent, three separate studies across a wide dose range in Cebus monkeys were conducted and compared with two studies of oral and parenteral haloperidol. METHODS: Twelve Cebus monkeys were tested with single i.m. doses of JL 13 (0.1-2.5 mg/kg), single p.o. doses (1.0-50.0 mg/kg), and 35 days of continuous p.o. (up to 25 mg/kg) treatments and were blindly evaluated. The same twelve monkeys were also tested with haloperidol i.m. (0.01-0.25 mg/kg) and nine of the monkeys also received haloperidol p.o. (0.1-5.0 mg/kg). Behaviors scored included sedation/arousal, locomotor activity, EPS of parkinsonism and dystonia, as well as reactivity. RESULTS: JL 13 produced mild to moderate and dose-related increased sedation and decreased locomotor activity. Minimal decreases in eye blinking rates were also noted as a consequence of sedation. Mild dystonia and parkinsonian symptoms of slow movement developed at the highest dose tested of 50 mg/kg p.o. in only 6 of 12 monkeys. This is 50 times higher than oral doses of haloperidol that would be needed to produce similar EPS effects. Dose-related EPS of dystonia and bradykinesia occurred in relation to decreased locomotor activity and reactivity to stimuli with haloperidol i.m. and p.o., which are features characteristically seen with traditional neuroleptics. CONCLUSIONS: The behavioral effects of JL 13 in non-human primates suggest this compound is well tolerated and may have a favorable antipsychotic benefit/risk ratio in the clinic, especially if antipsychotic efficacy occurs at doses well below those that can cause EPS.

Effects of benztropine on ketamine-induced behaviors in Cebus monkeys.

Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, causes a schizophrenic-like psychosis in normal volunteers and exacerbates psychotic symptoms in patients with schizophrenia. Recent work has shown that ketamine and other NMDA antagonists affect a range of behaviors in nonhuman primates, particularly those associated with motor and mental function such as attention and perception. Several lines of study also suggest that NMDA antagonists interact with cholinergic mechanisms. The effects of benztropine, an anticholinergic agent, on ketamine-induced behaviors were evaluated in a double-blind randomized test design in 20 Cebus monkeys. Benztropine (0.05, 0.1 and 0.25 mg/kg, i.m.) was injected 1 hour before ketamine (2.5 and 5.0 mg/kg, i.m.) administration. Behaviors scored for 90 minutes after ketamine administration included salivation, dystonia and reactivity to external stimuli. Benztropine almost completely blocked ketamine-induced hypersalivation, and partially ameliorated the dystonia syndrome by 50%, but did not affect ketamine-induced decreased reactivity to external stimuli. These results suggest that cholinergic mechanisms only moderately influence ketamine-induced central nervous system effects of motor dysfunction, and may not play a substantive role in the ketamine-induced deficit of reactivity to external stimuli, which involves a complex interaction of mental functions such as attention and perception, as well as motor behavior.

Clinical trial design issues in schizophrenic research.

Research studies are an indispensable tool in the Food and Drug Administration approval process. Becoming familiar with different research study designs helps one to understand and interpret the results of clinical trials. Research studies are undertaken with 2 major goals in mind: (1) to get a drug into registration (regulatory needs) and (2) to understand the clinical application of medicines (clinical application needs). This article discusses the 2 major goals of research studies, the design issues associated with those goals, and the design features of several recent comparative studies of atypical antipsychotics.

Antipsychotic-induced weight gain: a review of the literature.

With the availability of the so-called novel antipsychotic agents, extrapyramidal symptoms are becoming decreasingly problematic for patients with schizophrenia, and simultaneously, a new symptom is emerging as a preeminent concern. This side effect is weight gain and its metabolic concomitants. This article reviews what is currently known about antipsychotic-induced weight gain, describes the magnitude of the problem, briefly touches on mechanisms of action, and addresses the correlation of interindividual variations in magnitude of weight gain. In addition, we address questions about the effects of weight gain on compliance and whether or not there is a correlation between weight gain and therapeutic efficacy. Finally, we address medical consequences of weight gain and review the literature supporting various treatment options for antipsychotic-induced weight gain. As will be seen, this is an area of research in its infancy, and much work remains to be done.

The pharmacology of weight gain with antipsychotics.

In general, antipsychotic agents have diverse actions on a wide range of neurotransmitter systems. Data strongly suggest that a number of these systems may play a role in the regulation of body weight. In addition to having very distinct pharmacologic profiles, individual agents possess discrete weight gain liabilities. This article briefly reviews the evidence for the involvement of specific neurotransmitter systems in the control of body weight and describes the relevant pharmacologic characteristics of individual antipsychotic agents. By comparing the pharmacologic profiles of specific antipsychotic agents with their respective weight gain liabilities, this article attempts to gain an insight into the specific receptors underlying a drug's propensity to induce weight gain. However, there is still much to be learned concerning weight control mechanisms, and the role of many of the receptors at which antipsychotic agents are active remains unclear. In spite of this, an overview of current knowledge in the field may facilitate prediction of a potential novel antipsychotic agent's weight gain liability.

Estimating the consequences of anti-psychotic induced weight gain on health and mortality rate.

Many anti-psychotic medications produce marked weight gain. In this study, we estimate the expected impact of degrees of antipsychotic-induced weight gain on selected mortality rate and incidence rates of impaired glucose tolerance (IGT) and hypertension (HTN) among US adults. Using raw data from 5209 respondents from the Framingham Heart Study's public use data set and national statistics on population demographics, we estimated the expected effect of weight gain on number of deaths and incident cases of IGT and HTN for a 10-year period commencing in 1999. Results indicated that the estimated deleterious effects of weight gain were greater for people with higher BMIs at baseline, for greater degrees of weight gain, for men than women, and for older than younger persons. Because there is a 'U-shaped' relation between BMI and mortality rate, small to moderate weight gains among people with baseline BMIs less than 23 were predicted to decrease mortality rates, whereas weight gains among people with baseline BMIs above that level were expected to increase mortality rates. However, the relations of IGT and HTN with BMI are monotonically increasing. Thus, the anticipated effect of weight gain on IGT and HTN is deleterious regardless of baseline BMI. Because it is unclear whether the beneficial effects of the atypical agents on, for example, reducing suicide mortality, outweigh the putative increase in mortality due to weight gain, we estimate the beneficial effects due to decreased death from suicide with the potential deleterious effects due to a 10-kg weight gain. We found that 492 suicide deaths per 100,000 schizophrenic patients would be prevented over 10 years with the use of clozapine compared to 416 additional deaths due to antipsychotic induced weight gain. Although this estimate is rather crude and should be seen only as offering a sense of the likely situation, results suggest that the lives saved via clozapine may essentially be offset by the deaths due to weight gain. As we discuss, it is not possible to provide definitive estimates of the effect of antipsychotic-induced weight gain on health and mortality, but our findings suggest that the magnitude of weight gains induced by many antipsychotic agents is likely to have important deleterious effects on mortality and health.

Barriers to progress--the impact of tolerability problems.

Side-effects of antipsychotic treatment are important factors in patients' compliance with treatment regimens. Of particular relevance to compliance are extrapyramidal symptoms (EPS), sedation, weight gain and sexual dysfunction. The new, atypical antipsychotics offer several tolerability benefits over conventional neuroleptics, particularly with respect to EPS. However, differences in their receptor binding characteristics result in different side-effect profiles. All novel antipsychotics have a high 5-HT2 to D2 receptor binding ratio, which is postulated to be important for a low liability for EPS. Ziprasidone, a new antipsychotic in the late stages of clinical development, has a low affinity for some receptor types, activation of which has been linked with adverse events such as sedation, postural hypotension, weight gain and cognitive impairment; for example, ziprasidone has minimal activity at muscarinic (M1), histaminergic (H1) and alpha1-adrenergic receptors. In short- and long-term clinical trials, ziprasidone had a low liability for side-effects typically associated with poor compliance, such as EPS, weight gain and sexual dysfunction. The tolerability profiles of the new antipsychotics represent a major improvement over the older neuroleptics. The more favourable the benefit/risk ratios of these new drugs throughout all phases of treatment, the greater the likelihood that patients will have better outcomes.

Tardive dyskinesia: pathophysiology and animal models.

Tardive dyskinesia stimulated extensive research into the mechanisms of antipsychotic drug action. A wide range of homologous, analogous, and correlational animal models have been developed to explore how typical neuroleptic drugs do and atypical antipsychotic agents do not seem to cause tardive dyskinesia. The leading hypotheses of the underlying pathophysiology of tardive dyskinesia include dopamine receptor hypersensitivity, GABA insufficiency, and/or structural abnormalities. All these hypotheses have data both for and against them. The roles of psychosis and aging must also be considered in any explanation of tardive dyskinesia. The challenge still remains of how to accurately attribute the relative contributions of each of these factors to the pathogenesis and pathophysiology of tardive dyskinesia. Fortunately, the atypical antipsychotic agents appear to greatly decrease the liability of developing tardive dyskinesia, but how this occurs remains an open and fascinating line of inquiry.

Behavioral effects of ketamine, an NMDA glutamatergic antagonist, in non-human primates.

RATIONALE: The dopamine hypothesis is the most widely investigated theory underlying schizophrenia and the mechanisms of action for antipsychotic drugs. However, recent studies call into question this proposal. Thus, the focus has turned towards other mechanisms, one of which has been glutamatergic systems. Phencyclidine (PCP), a potent NMDA receptor antagonist, causes a schizophrenic-like psychosis in normal volunteers and exacerbates psychotic symptoms in patients with schizophrenia. Ketamine, like PCP, is a non-competitive NMDA receptor antagonist, which is short acting and has been used as a dissociative anesthetic as well as a research tool in psychosis. OBJECTIVE: To clarify the role of NMDA antagonists further and to develop an animal model of these actions, ketamine was studied across a range of behaviors in Cebus monkeys. METHODS: Thirty-two (six male, 26 female) Cebus monkeys, which were previously sensitized to neuroleptics, were tested with a wide range of doses of ketamine that spanned the clinical effect range from threshold effects to full anesthesia. Behaviors scored included sedation/arousal, locomotor activity, extrapyramidal symptoms of parkinsonism and dystonia, as well as reactivity. RESULTS: Ketamine produced dose-related increases in parkinsonian bradykinesia and dystonia as well as salivation. There were dose-related decreases in locomotor activity and reactivity to environmental stimuli. These effects had short time courses and steep dose-response curves. CONCLUSIONS: These results suggest that ketamine-induced behavioral effects in non-human primates offer a model for studying a glutamatergic role in motor and mental function such as attention or perception.

Extended lamivudine retreatment for chronic hepatitis B: maintenance of viral suppression after discontinuation of therapy.

In patients with chronic hepatitis B, brief lamivudine therapy suppresses hepatitis B virus (HBV) DNA but results infrequently in sustained losses of virus replication posttreatment. We evaluated treatment response and its posttreatment durability during up to 18 months of lamivudine therapy (100 mg/d) in 24 patients who had hepatitis B e antigen (HBeAg) despite 1 to 3 months of prior therapy. Therapy was to be stopped after HBeAg loss or seroconversion (acquisition of antibody to HBeAg); posttreatment monitoring continued for 6 months. During therapy, which was well tolerated, HBV DNA became undetectable in all evaluable patients, accompanied by reduced alanine transaminase (ALT) activity. The cumulative 18-month confirmed loss of HBeAg during therapy was 9 of 24 (38%) and seroconversion was 5 of 24 (21%). Therapy was discontinued after HBeAg loss/seroconversion in 7 patients, and HBeAg status was maintained in all. Four of the patients with HBeAg responses lost HBsAg at least once. In 10 (43%) of 23 patients tested, we identified HBV polymerase YMDD mutations, 3 with detectable HBV DNA (2 with ALT elevations) and 7 without virological/biochemical breakthrough. In conclusion, up to 18 months of lamivudine therapy was well tolerated, suppressed HBV replication consistently, and tripled the frequency of HBeAg losses observed during brief-duration therapy; HBeAg loss/seroconversion remained durable posttreatment. The emergence of YMDD-variant HBV was relatively common but occurred typically without reappearance of detectable HBV DNA or ALT elevation. Our observations suggest that lamivudine can be stopped after confirmed HBeAg loss or seroconversion.

Effect of a disease management tool on residents' compliance with American Diabetes Association standard of care for type 2 diabetes mellitus. American Diabetes Association.

Diabetes mellitus is the fourth leading cause of death in the United States and a major cause of blindness and heart disease. Often, physicians do not comply with American Diabetes Association standards of practice. We report improved resident physicians' compliance with American Diabetes Association (ADA) standards of care for patients with Type 2 diabetes mellitus after the implementation of a disease management tool for diabetes mellitus.

Tardive dyskinesia and atypical antipsychotic drugs.

Typical antipsychotic agents produce central nervous system effects, especially extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Nearly every patient who receives neuroleptic therapy has one or more identifiable risk factors for TD, among the most significant of which are older age, female gender, presence of EPS, diabetes mellitus, affective disorders, and certain parameters of neuroleptic exposure (i.e. dose and duration of therapy). The typical course of TD is a gradual onset after several years of drug therapy, followed by slow improvement or remission, but a large number of patients have persistent TD with irreversible symptoms. In the management of TD, the patient's mental status is of primary concern. Currently, no uniformly safe and effective therapies for TD exist, though a variety of therapeutic agents, including some of the atypical neuroleptics, have been reported to treat TD successfully in some patients. Because TD liability is so much lower with novel antipsychotic therapy, all patients who have TD or are at risk for TD, as well as EPS, should be considered candidates for switching to these new drugs.

Effects of clozapine therapy in schizophrenic individuals at risk for tardive dyskinesia.

Neuroleptics were the first modern class of pharmacotherapeutic agents available for the treatment of schizophrenia. Although they were effective in reducing florid psychotic symptoms, up to 90% of treated individuals subsequently developed extrapyramidal symptoms (EPS) (akathisia, dystonia, or parkinsonism), and about 20% developed tardive dyskinesia (TD). When clozapine became commercially available for treatment-resistant and treatment-intolerant (i.e., prone to EPS and TD) schizophrenic individuals, it became apparent that an antipsychotic need not induce motor side effects to be efficacious in reducing the symptomatology of schizophrenia. Sociodemographic, behavioral, and clinical predictors of TD are useful in identifying a subset of schizophrenic individuals who would benefit from treatment with clozapine, the prototype atypical antipsychotic whose efficacy and motor side effect profile are superior to those of chlorpromazine. This favorable motor side effect profile of clozapine contributes to improved patient outcomes by reducing noncompliance, substance abuse, and suicide, resulting in improved quality of life and savings on health care costs.

Will the new antipsychotics bring hope of reducing the risk of developing extrapyramidal syndromes and tardive dyskinesia?

Treatment of psychotic symptoms with traditional neuroleptics has been complicated by acute extrapyramidal syndromes (EPS) and late occurring tardive dyskinesia. These widely prevalent disorders have both motor and mental components which impose additional impairments on patients who are already substantially limited by their psychoses. Research activities with new drugs involve multiple neurotransmitters and different receptor subtypes. These new approaches have produced an increasingly desirable group of antipsychotic agents with a low EPS profile. The initial advances in low EPS with clozapine and risperidone are being followed up with further gains using agents such as sertindole, olanzapine and seroquel. The advent of these new agents seems likely to fulfill the promise that it is possible to have antipsychotic agents with a low EPS liability, and possibly a low risk of tardive dyskenesia.

The relationship of pharmacology to side effects.

Most traditional neuroleptics have a narrow therapeutic-to-toxic index, and thus, the novel antipsychotics are the result of a search to substantially widen the distance between the dose that treats psychosis and the one that produces adverse effects. In vitro binding profiles have been created for the atypical antipsychotics that have been approved by the U.S. Food and Drug Administration (FDA)-clozapine, olanzapine, and risperidone and those that are under FDA review-quetiapine and sertindole. These profiles, which were compared with that of the typical neuroleptic haloperidol, provide guidance for predicting the adverse effects produced by these drugs. Most conventional antipsychotics have central nervous system effects, particularly extrapyramidal symptoms (EPS) and tardive dyskinesia, sedation, and dulling of cognition. Other adverse effects of the typical antipsychotics include the neuroleptic malignant syndrome, orthostatic hypotension, changes in liver function, anticholinergic and antiadrenergic side effects, sexual dysfunction, and weight gain. The newer agents have a lower incidence of EPS and tardive dyskinesia, while weight gain and changes in blood pressure and liver function tests are adverse effects that have been associated with the use of the newer agents. The favorable side effect profile of these new antipsychotics is likely to make patients more willing to continue treatment, and thus these agents represent a step forward in the treatment of patients with severe, chronic mental illness.

Neuroleptic intolerance.

This article reviews antipsychotic medication side effects, especially those that require the physician to discontinue or the patient to be noncompliant with otherwise useful medication. They include such common problems as extrapyramidal syndromes (dystonia, akathisia, drug-induced Parkinsonism, tardive dyskinesia), sedation, weight gain, and sexual dysfunction, as well as less frequent concerns, such as seizures, neuroleptic malignant syndrome, agranulocytosis, torsade de pointes, hepatitis, and dermatological and ophthalmological syndrome. The adverse events associated with some of the new antipsychotic drugs are included. Available information about individual susceptibility to side effects is addressed by syndrome.