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Few long-term studies have compared the efficacy and safety of typical and atypical antipsychotic medications directly in patients with a first episode of psychosis who met the criteria for schizophrenia or a related psychotic disorder. This study compared the acute and long-term effectiveness of haloperidol with that of olanzapine in patients with first-episode psychosis in a large, controlled clinical trial.Patients with first-episode psychosis (N=263) were randomly assigned under double-blind conditions to receive haloperidol or olanzapine and were followed for up to 104 weeks. Domains measured included psychopathology, psychosocial variables, neurocognitive functioning, and brain morphology and metabolism. This report presents data from clinical measures of treatment response and safety data from the 12-week acute treatment phase.Haloperidol and olanzapine were associated with substantial and comparable baseline-to-endpoint reductions in symptom severity, which did not differ significantly in last-observation-carried-forward analyses. However, in a mixed-model analysis, olanzapine-treated subjects had significantly greater decreases in symptom severity as measured by the Positive and Negative Syndrome Scale total score and negative and general scales and by the Montgomery-Asberg Depression Rating Scale but not as measured by the Positive and Negative Syndrome Scale positive scale and by the Clinical Global Impression severity rating. Olanzapine-treated patients experienced a lower rate of treatment-emergent parkinsonism and akathisia but had significantly more weight gain, compared with the haloperidol-treated patients. Overall, significantly more olanzapine-treated subjects than haloperidol-treated subjects completed the 12-week acute phase of the study (67% versus 54%).As expected on the basis of previous studies, both olanzapine and haloperidol were effective in the acute reduction of psychopathological symptoms in this group of patients with first-episode psychosis. However, olanzapine had several relative advantages in therapeutic response. Although the nature of adverse events differed between the two agents, retention in the study was greater with olanzapine. Retention in treatment is important in this patient population, given their risk of relapse. Longer-term results are needed to determine whether treatment with atypical antipsychotics results in superior outcomes for a first episode of schizophrenia.

The authors provide a detailed clinical description of minor depression: its symptoms, level of disability, stability, and relationship to patient and family history of major depressive disorder.Rigorous criteria for minor depression, including functional disability, were used to identify 226 individuals for a three-phase treatment study. This report presents data obtained on that study group during the first study phase, a 4-week placebo lead-in period.One hundred sixty-two subjects (72% of the initial study group) remained in the study for 4 weeks and continued to meet criteria for minor depression. Minor depression in these subjects was primarily characterized by mood and cognitive symptoms, not the classical neurovegetative signs and symptoms of depression. Approximately one-third of the subjects with minor depression had a past history of major depressive disorder, and nearly half had a family history of unipolar depressive disorder; however, neither factor affected the severity or quality of minor depressive symptoms.These data suggest that 1) minor depression is not evanescent; 2) minor depression is characterized by mood and cognitive symptoms rather than neurovegetative symptoms; 3) minor depression may occur either independently of a lifetime history of major depressive disorder or as a stage of illness in the course of recurrent unipolar depressive disorder; and 4) depressive disorders should be conceptualized as a continuum of severity.

OBJECTIVE: The primary intent of this study was to compare the efficacy and safety of olanzapine and placebo in the treatment of acute mania. METHOD: The design involved a random-assignment, double-blind, placebo-controlled parallel group study of 3 weeks’ duration. After a 2- to 4-day screening period, qualified patients were assigned to either olanzapine (N=70) or placebo (N=69). Patients began double-blind therapy with either olanzapine, 10 mg, or placebo given once per day. After the first day of treatment, the daily dose could be adjusted upward or downward, as clinically indicated, by one capsule (olanzapine, 5 mg/day) within the allowed range of one to four capsules. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. Clinical response was defined a priori as a decrease of 50% or more from baseline in Young Mania Rating Scale total score. RESULTS: The olanzapine group experienced significantly greater mean im...

Objective:Although panic attacks account for only a portion of the morbidity of panic disorder and panic attack frequency assessments are unreliable, studies of drug efficacy in panic disorder have generally used reduction in panic attack frequency as the primary measure of improvement. The authors studied the efficacy of fluoxetine treatment in panic disorder and measured the relative contributions of changes in symptoms to overall improvement.Method:Patients with a diagnosis of panic disorder (N=243) were randomly assigned to treatment with 10 or 20 mg/day of fluoxetine or placebo. Primary outcome measures were change in panic attack frequency and clinician-rated Clinical Global Impression improvement scores. Other assessments included a panic attack inventory, clinician-rated and patient-rated versions of the Panic and Phobic Disorder Change Scale, a phobia rating scale, the Hamilton Anxiety Rating Scale, the 21-item Hamilton Depression Rating Scale, and the Sheehan Disability Scale. Correlations were ...

Objective: Tardive dyskinesia is a serious and common complication of neuroleptic treatment. Olanzapine is a novel antipsychotic agent exhibiting regional mesolimbic dopaminergic selectivity and a broad-based pharmacology encompassing serotonin, dopamine, muscarinic, and adrenergic receptor binding affinities. The authors’ goal was to compare the incidence of tardive dyskinesia among patients receiving olanzapine and those receiving the conventional dopamine 2 antagonist haloperidol. Method: Data were analyzed from three actively controlled and blind long-term responder studies of subjects meeting DSM-III-R criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder treated with olanzapine (N=707, up to 20 mg/day, 237 median days of exposure) or haloperidol (N=197, up to 20 mg/day, 203 median days of exposure) who did not have evidence of tardive dyskinesia at baseline. All of the subjects had a chronic disease course (mean greater than 10 years), and there were no significant between-treatment group differences in demographic or disease characteristics. The Abnormal Involuntary Movement Scale and research diagnostic criteria for tardive dyskinesia were used to define the comparative incidence rates of long-term treatmentemergent tardive dyskinesia. Results: The incidence of newly emergent tardive dyskinesia at any visit after baseline, at the final visit, and at the final two clinical assessments was statistically significantly lower among olanzapine-treated patients than among haloperidol-treated patients. Conclusions: These findings support an atypical extrapyramidal symptom profile and the potential of a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol among patients requiring maintenance antipsychotic treatment. (Am J Psychiatry 1997; 154:1248‐1254)

OBJECTIVE The authors investigated whether primary negative symptoms of schizophrenia are enduring or treatment-responsive. METHODS Previously, a double-blind, random-assignment trial of the novel antipsychotic olanzapine (in low, medium, and high dose ranges), placebo, or haloperidol (10-20 mg/day) for 335 schizophrenic inpatients was conducted for up to 52 weeks. Changes in the treatment groups from baseline to endpoint in summary scores on the Scale for the Assessment of Negative Symptoms (SANS) and several secondary measures were compared. This article describes a path analysis to determine to what extent the total treatment effect on negative symptoms was direct or indirect (i.e., mediated by differential effects on positive symptoms, extrapyramidal symptoms, or mood). RESULTS Significantly greater improvement was achieved with high-dose olanzapine than with placebo or haloperidol. Olanzapine had a significantly greater direct effect than placebo on all SANS dimensions except anhedonia-asociality. Olanzapine also demonstrated a significantly greater direct effect than haloperidol on negative symptoms, especially on the dimensions of affective flattening and avolition-apathy. Olanzapine's superior effects were replicated in a subgroup with SANS-defined prominent negative symptoms (N = 116) and a subgroup with a BPRS-defined cross-sectional proxy for the deficit state (N = 117). CONCLUSIONS These results suggest that the negative symptoms of schizophrenia are directly responsive to treatment. The significantly greater direct and indirect effects of olanzapine than of haloperidol on negative symptoms are likely related to olanzapine's pleotrophic pharmacology, which includes dopaminergic, serotonergic, muscarinic, and adrenergic activities. The results contribute to the hypothesis that negative symptoms may be under the influence of several neurotransmitters within one or more neuroanatomic circuits.

The authors analyzed the dexamethasone suppression test (DST) results of 54 patients with major depressive disorder in relation to their pre-DST levels of cholesterol, sodium, potassium, and blood glucose, which are thought to have adrenocorticotrophic links. Discriminant analysis revealed that sodium alone was a significant predictor of nonsuppression. Validation of the predictive power of sodium could minimize the need for DST administration.

After taking the lifetime migraine headache histories of 116 patients with major depressive disorder, the authors compared the prevalence of migraine headaches in these depressed patients with the prevalence of migraine reported in four community surveys. There was a trend for the depressed men to experience a higher prevalence of migraine than men in the general population, but the depressed women had a migraine prevalence similar to that of women in the general population. No differences on multiple variables of depressive illness were found between depressed patients with a history of migraine and those with none.

Seventy-one patients with major depression or an anxiety disorder were treated with benzodiazepines. They were followed prospectively for evidence of misuse or abuse. There was no evidence of benzodiazepine abuse. Five patients (all with major depression) misused their benzodiazepines.