Antiglucocorticoid treatment of depression: double-blind ketoconazole. Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Comparative efficacy and safety of atypical and conventional antipsychotic drugs in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol. Amisulpride versus haloperidol in treatment of schizophrenic patients--results of a double-blind study. Zuclopenthixol and haloperidol in patients with acute psychotic states. A double-blind, multi-centre study. A double-blind, placebo-controlled study of nortriptyline and bromocriptine in male alcoholics subtyped by comorbid psychiatric disorders. Alprazolam, amitriptyline, doxepin, and placebo in the treatment of depression. Mifepristone versus placebo in the treatment of psychosis in patients with psychotic major depression. Antidepressants in 'depressed' schizophrenic inpatients. A controlled trial.
Hypercortisolemia is frequently observed in major depression but its pathophysiologic significance is unknown. In patients in whom hypercortisolism contributes to depressive symptomatology, antiglucocorticoid agents should have antidepressant effects.
                Twenty medication-free depressed patients (eight of whom were hypercortisolemic and twelve of whom were not) received either the cortisol biosynthesis inhibitor, ketoconazole (400-800 mg/d p.o.) or placebo for 4 weeks in a double-blind manner, and behavioral ratings were performed weekly.
                Ketoconazole, compared to placebo, was associated with improvements in depression ratings in the hypercortisolemic, but not in the non-hypercortisolemic patients. The hormonal changes seen (decreased dehydroepiandrosterone and testosterone levels and increased pregnenolone and pregnenolone-sulfate levels) are consistent with enzymatic blockade of C17,20-lyase, 11-hydroxylase, and 17-hydroxylase. Ketoconazole was generally well tolerated with no occurrence of significant side effects or laboratory abnormalities.
                This small-scale double-blind study suggests that antiglucocorticoids have antidepressant activity in hypercortisolemic depressed patients. The data are consistent with a causal role of adrenocortical dysfunction in some depressed patients and suggest the need for larger-scale trials. High cortisol levels are found in severe mood disorders, particularly bipolar disorder. Hypercortisolaemia may cause or exacerbate both neurocognitive impairment and depressive symptoms. We hypothesized that antiglucocorticoid treatments, particularly corticosteroid receptor antagonists, would improve neurocognitive functioning and attenuate depressive symptoms in this disorder. To test this hypothesis, 20 bipolar patients were treated with 600 mg/day of the corticosteroid receptor antagonist mifepristone (RU-486) or placebo for 1 week in a double-blind crossover design. Over the total 6 weeks of the study, neurocognitive and neuroendocrine function were evaluated at baseline, days 21 and 42. Mood symptoms were evaluated weekly. Nineteen subjects completed the protocol; there were no drop-outs due to adverse events. Following treatment with mifepristone, selective improvement in neurocognitive functioning was observed. Spatial working memory performance was significantly improved compared to placebo (19.8% improvement over placebo). Measures of verbal fluency and spatial recognition memory were also improved after mifepristone. Beneficial effects on mood were found; Hamilton Depression Rating Scale scores were significantly reduced compared to baseline (mean reduction of 5.1 points) as were Montgomery-Asberg Depression Rating Scale scores (mean reduction of 6.05 points). No significant change occurred after placebo. These data require replication but provide preliminary evidence that glucocorticoid receptor antagonists may have useful cognitive-enhancing and possibly antidepressant properties in bipolar disorder. 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. In a double-blind study, 41 schizophrenic patients (ICD, 9th rev.) were divided into two groups. With a flexible dose, twenty patients were treated with haloperidol, twenty-one with amisulpride. With respect to relevant criteria such as age, sex, length and degree of illness, the two groups were comparable. The study was conducted over 42 days. As early as within the first 14 days, both groups showed significant improvement with respect to their psychotic symptoms. When the two groups were compared on the basis of the BPRS subscore for the anxiety-depression syndrome, and the AMDP system subscores for the somatic-depressive syndrome and the hypochondriac syndrome, the amisulpride group showed significantly better results than the haloperidol group. The ratings on the EPS scales of Webster and Simpson revealed significantly fewer extrapyramidal side-effects in the amisulpride group. Psychotic symptoms were improved after both types of treatment. Amisulpride treatment showed better results with regard to depressive symptoms, and less tendency to generate extrapyramidal side-effects. A double-blind, multi-centre study was carried out in 49 hospitalized patients with an acute psychosis or an exacerbation of a chronic psychosis to compare the wanted and unwanted effects of the neuroleptics, zuclopenthixol and haloperidol. Patients were allocated at random to receive treatment with one or other of the trial drugs for 8 weeks or until discharge. Five patients on zuclopenthixol and 6 on haloperidol were excluded from the efficacy analyses because they did not complete a minimum of 4-weeks' treatment. Dosage was chosen and adjusted to the individual patient's condition and response. The average daily doses in Week 4 were 33.5 mg and 10.3 mg, respectively. Clinical assessments, including CGI, BPRS and the UKU side-effect scale, were done at baseline, and after 1, 2, 4, 6 and 8 weeks of treatment or at discharge if the patient was discharged earlier than Week 8. Both treatments caused a significant reduction in scores with no between-group differences. More patients in the zuclopenthixol group were discharged early indicating slightly more rapid onset of action. Zuclopenthixol caused a significantly greater improvement in 'anxious-depression' factor score than haloperidol. The most frequent unwanted effects were extrapyramidal symptoms and there were no significant differences between the groups. The extrapyramidal symptoms tended to be transient in the zuclopenthixol group, but not in the haloperidol group. The study confirmed that both zuclopenthixol and haloperidol were effective drugs in the treatment of acute, psychotic patients. There was a trend towards a slightly more rapid onset of effect and a somewhat stronger anxiolytic-antidepressant effect by zuclopenthixol compared to haloperidol. This double-blind, placebo-controlled, 6-month follow-up treatment study investigated the efficacy of bromocriptine and nortriptyline in attenuating drinking behavior and psychiatric symptoms in 216 male alcoholic patients subtyped by comorbid psychiatric disorder(s). Three well-defined subtypes were examined: alcoholism only, alcoholism + affective/anxiety disorder, and alcoholism + antisocial personality disorder. It was hypothesized that both medications would relieve negative affective symptoms associated with alcohol use and would be particularly effective for the affective/anxiety subgroup. Contrary to our predictions, the only significant effects found were with the antisocial personality disorder patients who were receiving nortriptyline. One interpretation of the results was that nortriptyline may have reduced impulsive drinking in the antisocial personality disorder subgroup by actions on serotonergic neurotransmission. Five hundred four outpatients suffering from a major depressive episode were randomly assigned to receive either amitriptyline, doxepin, alprazolam, or placebo. The study was conducted in three treatment centers during a six-week period. All three active medications produced significantly more clinical improvement than did placebo, irrespective of the patient's initial anxiety, depression, and psychomotor retardation and irrespective of the patient's assignment to various subtypes of depression, including the DSM-III melancholia subtype. Compared with placebo, sedation was reported more frequently with all three medications, whereas anticholinergic effects were reported more frequently only for the two tricyclic antidepressants, but not for alprazolam. Abnormalities in the hypothalamic pituitary adrenal axis have been implicated in the pathophysiology of psychotic major depression (PMD). Recent studies have suggested that the antiglucocorticoid, mifepristone might have a role in the treatment of PMD. The current study tested the efficacy of mifepristone treatment of the psychotic symptoms of PMD.
                221 patients, aged 19 to 75 years, who met DSM-IV and SCID criteria for PMD and were not receiving antidepressants or antipsychotics, participated in a double blind, randomized, placebo controlled study. Patients were randomly assigned to either 7 days of mifepristone (n = 105) or placebo (n = 116) followed by 21 days of usual treatment.
                Patients treated with mifepristone were significantly more likely to achieve response, defined as a 30% reduction in the Brief Psychiatric Rating Scale (BPRS). In addition, mifepristone treated patients were significantly more likely to achieve a 50% reduction in the BPRS Positive Symptom Scale (PSS). No significant differences were observed on measures of depression.
                A seven day course of mifepristone followed by usual treatment appears to be effective and well tolerated in the treatment of psychosis in PMD. This study suggests that the antiglucocorticoid, mifepristone, might represent an alternative to traditional treatments of psychosis in psychotic depression. Fifty-eight actively psychotic inpatients who initially met criteria for long-standing schizophrenia and subsequently met Research Diagnostic Criteria for a current episode of schizoaffective disorder (mainly schizophrenic) with a depressive syndrome, and who scored at least 30 (mean = 55, SEM = 1.6) on the Brief Psychiatric Rating Scale and 17 (mean = 23, SEM = 0.7) on the Hamilton Rating Scale for Depression, were treated for 5 weeks with haloperidol hydrochloride and benztropine. Haloperidol and benztropine treatment was continued, while those patients who consistently scored greater than 17 on the Hamilton Rating Scale for Depression were randomly assigned to the following double-blind treatment groups for 4 weeks: adjunctive amitriptyline hydrochloride, desipramine hydrochloride, or placebo. Adjunctive desipramine or amitriptyline showed no significant therapeutic advantage, when compared with haloperidol and placebo, on the Brief Psychiatric Rating Scale or the Hamilton Rating Scale for Depression. After 4 weeks of combine therapy, patients receiving adjunctive amitriptyline or desipramine, as compared with those receiving adjunctive placebo, tended to score higher on the Brief Psychiatric Rating Scale hallucinatory behavior item and on the thinking disturbance factor than patients receiving placebo. These results suggest that adjunctive antidepressants are not indicated for the treatment of depressive symptoms in actively psychotic schizophrenic inpatients. Adjunctive antidepressants may retard the rate of resolution of psychosis in this population.
The use of antiglucocorticoids in the treatment of mood disorders is at the proof-of-concept stage. Considerable methodological differences exist between studies with respect to the compounds used and the patient cohorts studied. Results in some diagnostic subtypes are promising and warrant further investigation to establish the clinical utility of these drugs in the treatment of mood disorders.