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Existing obesity therapies are limited by safety concerns and modest efficacy reflecting a weight loss plateau. Here, we explore combination therapy with bupropion (BUP), a putative stimulator of melanocortin pathways, and an opioid antagonist, naltrexone (NAL), to antagonize an inhibitory feedback loop that limits sustained weight reduction. In vitro electrophysiologic experiments were conducted to determine the extent to which BUP+NAL stimulated hypothalamic pro-opiomelanocortin (POMC) neurons in mouse brain. A subsequent study further characterized the effect of combination BUP+NAL treatment on food intake in lean and obese mice. Finally, a randomized, blinded, placebo-controlled trial in obese adult subjects was conducted. Randomization included: BUP (300 mg) + NAL (50 mg), BUP (300 mg) + placebo (P), NAL (50 mg) + P or P+P for up to 24 weeks. BUP+NAL stimulated murine POMC neurons in vitro and caused a greater reduction in acute food intake than either monotherapy, an effect consistent with synergism. Combined BUP+NAL provided sustained weight loss without evidence of an efficacy plateau through 24 weeks of treatment. BUP+NAL completers diverged from NAL+P (P < 0.01) and P+P (P < 0.001) at week 16 and from BUP+P by week 24 (P < 0.05). The combination was also well tolerated. Translational studies indicated that BUP+NAL therapy produced synergistic weight loss which exceeded either BUP or NAL alone. These results supported the hypothesis that NAL, through blockade of β-endorphin mediated POMC autoinhibition, prevents the classic weight loss plateau observed with monotherapies such as BUP. This novel treatment approach (BUP+NAL) holds promise for the treatment of obesity.

The novel antipsychotic agent olanzapine (Zyprexa, Eli Lilly and Company) is a thienobenzodiazepine analog marketed for the treatment of schizophrenia. Olanzapine's diverse receptor binding profile and greater affinity for serotonin receptors over dopamine receptors is thought to impart antipsychotic efficacy with a low incidence of serious extrapyramidal symptoms (EPS). With once daily dosing steady-state plasma concentrations reached within approximately 1 week. Olanzapine is extensively metabolized by the liver, is mostly excreted in the urine, and has few drug intractions. In clinical trials, the efficacy of olanzapine for treating schizophrenia is better than placebo and haloperidol and comparable to risperidone. Olanzapine may also ameliorate some comorbid symptoms including negative symptoms, depression, anxiety, substance abuse, and cognitive dysfunction, and it is effective in the long-term maintenance of response, treatment-resistance, and improving quality of life. The overall direct costs are lower with olanzapine treatment compared with haloperidol or risperidone treatment. In clinical trials, olanzapine demonstrates a favorable safety profile. The most frequently reported treatment-emergent adverse events are somnolence, schizophrenic reaction, insomnia, headache, agitation, rhinitis, and weight gain. Significantly fewer EPS (based on formal rating scales) and incidences of tardive dyskinesia have been reported for olanzapine compared with haloperidol. Olanzapine has not been associated with persistent elevations of prolactin above the upper limit of normal nor has it been associated with clinically significant changes in cardiac QTc interval. Fewer incidences of suicide attempts have been reported with olanzapine compared with placebo, haloperidol, or risperidone treatments. There is evidence that olanzapine may be effective in the treatment of mood disorders, psychosis associated with Alzheimer's disease, obsessive-compulsive disorder, pervasive developmental disorders, and delirium. Patients with schizophrenia have been successfully switched from other antipsychotics to olanzapine. In conclusion, olanzapine offers a significantly improved risk-to-benefit profile compared with haloperidol and possibly risperidone, and thus should be considered an important treatment option for schizophrenia and related disorders. SUMMARY Olanzapine is an innovative pharmaceutical product that has been prescribed to more than four million individuals worldwide. Olanzapine has a diverse neurotransmitter receptor binding profile that is similar to clozapine, with selective affinity for the serotonin receptors over the dopamine receptors. In vitro and in vivo preclinical experimentation has provided evidence for the antipsychotic efficacy of olanzapine with a low incidence of serious EPS. In addition, olanzapine has a pharmacokinetic profile that allows for single daily dosing and has minimal metabolic interactions with commonly coadministered medications. Through its distinct pharmacology, olanzapine offers patients a significantly improved risk-benefit profile. Across the diverse series of clinical studies discussed in this review, olanzapine has helped to redefine the expectations for the pharmacotherapy of schizophrenia. Olanzapine (5 to 20 mg/day) has demonstrated an improvement in total psychopathology, which was significantly greater than that seen with placebo or the active comparator, haloperidol. This effect was comprised of at least comparable benefits to haloperidol on positive psychotic symptoms and superior results for the more chronic and disabling features of negative, concurrent anxious and depressive, and cognitive symptoms. This broadened range of treatment-responsive symptoms is complemented by a greater depth of clinical response as well. Given the historical challenge of compliance with the older antipsychotic drugs, it is also noteworthy that these outcomes were achieved with an adverse event discontinuation rate similar to placebo. Compared with conventional antipsychotic agents, the incidence of troublesome EPS or hyperprolactinemia was low. Studies in special populations (i.e., the geriatric patient) appear to confirm this safety profile. Because schizophrenia is a chronic disease, controlled and blinded maintenance studies showing the superiority of olanzapine to placebo or active comparators (haloperidol, risperidone) are also reassuring, especially in the context of the long-term safety experience with olanzapine. In particular, data suggesting a lower incidence of potentially irreversible movement disorders, such as tardive dyskinesia, are striking and of importance to treatment decision makers. Moreover, these advantages appear to translate into improved quality of patient life, increased functional well-being (i.e., return to work), and an overall reduction in the total direct cost of managing schizophrenia. While further studies are ongoing, the data on olanzapine in mood disorders and psychosis associated with Alzheimer's disease are encouraging. Additional studies evaluating olanzapine in nonschizophrenic disorders are awaited. As more “atypical” agents enter the marketplace, head-to-head comparisons are encouraged to properly evaluate the relative merits of each compound. Experience to date tells us that the newer agents to treat psychosis are not all alike. Based on the clinical review in this paper, olanzapine does seem to represent a novel and compelling first-line option for the management of psychotic disorders.

Obesity is a major health care concern because of its associated medical complications and increased mortality. Despite a myriad of short-term weight loss strategies and the motivation of improving health, patients have difficulty maintaining reduced weight. Pharmacologic agents, such as fluoxetine, a selective serotonin uptake inhibitor, have been investigated as adjunctive therapy to standard weight management programs. Extended therapy with fluoxetine has demonstrated clinically meaningful benefits on weight loss and obesity-associated medical conditions in double-blind placebo-controlled studies. However, the magnitude of these benefits for individuals vary. Such findings are consistent with the belief that the obesity syndrome has differing etiologies. Accordingly not all patients are likely to benefit from a particular therapy. Studies should identify patient subgroups that are more likely to respond to a specific therapy. In this study of 719 fluoxetine-treated and 722 placebo treated patients in four multicenter, randomized, double-blind, long-term clinical trials, we investigated possible predictors of a beneficial long-term outcome from fluoxetine therapy. Patients' age, current smoking activity, and baseline uric acid concentration were predictors of a meaningful long-term treatment effect. Further review of the weight loss patterns of patients achieving long-term success provided the basis for a treatment monitor. Use of the predictors and the treatment monitor are strategies to maximize the benefits of therapy through improved patient selection and monitoring during a therapeutic program.

We investigated 243 patients from a series of comparator and/or placebo-controlled, double-blind trials of several mechanistically distinct antidepressants. Data were analyzed for changes in suicidal ideation during trial participation. Ambulatory referrals with a current DSM-III-R major depression, corroborated by a structured interview, were screened; those fulfilling entrance criteria began a 1-week, single-blind placebo run-in. Pool 1 (placebo comparator) subjects who continued to meet entrance criteria at their baseline visit were blindly randomized to receive either placebo (n = 49) or one of several novel antidepressant drugs (n = 81). Pool 2 subjects (active comparator) were randomized to either a novel antidepressant (n = 66) or a tricyclic antidepressant comparator (n = 57). Trial duration ranged from 5 to 8 weeks. Patient compliance was monitored by a regular pill count from each subject's blister pack. Analyses were conducted on Pool 1 and Pool 2 separately. Ego-dystonic suicidal preoccupation or acts were not reported in either group. There was a statistically significant treatment difference in Hamilton Depression Rating Scale item 3 mean peak change (Pool 1); patients treated with a novel antidepressant demonstrated a mean decrease in HDRS item 3 (improvement), those patients randomized to placebo experienced a mean score increase (worsening). No statistically significant treatment difference in mean peak change difference factors (CDFs) between the novel antidepressants and conventional tricyclic antidepressant comparators (Pool 2) was observed. A statistically significant correlation between item 3 change and total HDRS-17 change also emerged (both treatments within each pool). Increased suicidal ideas/behaviors may emerge during depression “treatment.” However, in this study it occurred more frequently among placebo recipients, suggesting a change in suicidal ideation was a reflection of the underlying disease process. Not surprisingly, antidepressants improved suicidal ideation to a greater extent than placebo. Depression 2:73–79 (1994). © 1994 Wiley-Liss, Inc.

Unexpected clinical worsening has been described anecdotally during pharmacotherapy for depression. We analyzed data front 7,974 patients in double-blind, controlled trials (fluoxetine, placebo, tricyclics; mood/nonmood disorders). Paradoxical worsening with placebo either exceeded (bulimia nervosa, obesity) or was comparable (depression, obsessive-compulsive disorder) to that with fluoxetine or tricyclics. Paradoxical worsening appears to be part of the disease course, not uniquely the result of pharmacotherapy. Depression 1:105–107(1993). © 1993 Wiley-Liss, Inc.