Edward Amico

A placebo-controlled crossover trial of d-cycloserine added to clozapine in patients with schizophrenia

BACKGROUND D-Cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor, has previously been shown to improve negative symptoms when added to conventional antipsychotics and, in one preliminary dose-finding study, worsened negative symptoms when added to clozapine. METHODS Seventeen schizophrenia outpatients treated with clozapine were assigned in random order to 6-week trials of D-cycloserine 50 mg/day and placebo in a crossover design separated by a 1 week placebo washout. RESULTS Eleven patients competed the 13-week study. D-Cycloserine significantly worsened ratings of negative symptoms compared to placebo but did not significantly affect ratings of psychotic symptoms. CONCLUSIONS The differing effects of D-cycloserine on negative symptoms when added to clozapine compared to conventional antipsychotics suggests that activation of the glycine recognition site may play a role in clozapines efficacy for negative symptoms.

A placebo-controlled trial of fluoxetine added to neuroleptic in patients with schizophrenia.

Following a 2-week placebo lead-in, schizophrenic patients were randomly assigned to fluoxetine 20 mg/day or placebo added to depot neuroleptic for a 6-week, double blind trial. All patients had received a stable dose of depot neuroleptic for at least 6 months and did not meet criteria for depression. Serum samples were obtained at baseline and at weeks 4 and 6. Scores on the negative symptom subscale of the Brief Psychiatric Rating Scale (BPRS) were significantly lower at week 6, controlling for baseline scores, in patients receiving fluoxetine (n=20) compared to patients receiving placebo (n=21). Measures of psychosis, depression, global functioning and extrapyramidal symptoms (EPS) did not differ between groups at week 6. Fluoxetine administration was associated with a mean 65% increase in serum fluphenazine concentrations in 15 patients and a mean 20% increase in serum haloperidol concentrations in three patients. The change in negative symptoms at week 6 did not correlate with serum concentrations of fluoxetine or norfluoxetine, but did inversely correlate withS-norfluoxetine, an active stereoisomer of fluoxetine. For these chronically ill patients, fluoxetine significantly improved negative symptoms and did not worsen EPS, despite causing substantial elevation in serum concentrations of neuroleptics.

Self-reports of childhood abuse in chronically psychotic patients

A heterogeneous sample of 61 chronically psychotic patients were subgrouped according to the presence or absence of a self-reported history of childhood abuse. Patients reporting childhood abuse (n = 27) had an earlier age of onset, scored higher on the Dissociative Experiences Scale, reported more amnesia, and relapsed more frequently than patients not reporting abuse histories. Histories of childhood abuse and of past stimulant abuse predicted the score on the Dissociative Experiences Scale. A history of childhood abuse may thus contribute to the symptomatology and course of illness in some chronically psychotic patients.

An open trial of buspirone added to neuroleptics in schizophrenic patients.

Twenty chronic schizophrenic patients completed at least 2 weeks of a 6-week trial of buspirone (mean dose 23.8 mg/day) added to a stable dose of neuroleptic. At week 6, mean scores were significantly improved (p less than 0.01) on the Brief Psychiatric Rating Scale, the Simpson Angus Scale for Extrapyramidal Symptoms and the Global Assessment Scale. Overall measures of akathisia and tardive dyskinesia were not significantly changed at week 6. In the 7 patients taking oral haloperidol, mean plasma concentrations of haloperidol were significantly increased (p less than 0.05) by 26% 6 weeks after adding buspirone.

Clozapine treatment increases serum glutamate and aspartate compared to conventional neuroleptics

SummaryTo examine whether serum excitatory amino acid concentrations change with clozapine treatment and whether these changes correlate with improvement in negative symptoms, serum excitatory amino acids were measured and clinical scales administered in seven subjects with schizophrenia before and after switching from conventional neuroleptics to clozapine. Clozapine treatment was associated with increased serum glutamate and aspartate concentrations. Clinical improvement was negatively correlated with baseline glycine concentrations. These results support the hypothesis that clozapine acts at least in part by increasing glutamatergic activity.

A placebo-controlled trial of selegiline (l-deprenyl) in the treatment of tardive dyskinesia☆

The goal of this study was to determine whether selegiline (L-deprenyl), a selective monoamine oxidase B inhibitor and antioxidant, would improve neuroleptic-induced tardive dyskinesia (TD). Thirty-three patients with TD were randomly assigned to selegiline 10 mg/day or placebo for 6 weeks and were assessed at baseline and at weeks 1, 2, 4, and 6 for TD, parkinsonism, akathisia, depression, and positive and negative symptoms. Examinations for TD were videotaped and scored by a rater unaware of the temporal sequence of examination. Twenty-eight subjects completed at least 1 week of treatment; all five dropouts were receiving selegiline. When baseline score and gender were controlled, the group receiving selegiline displayed significantly less improvement of TD compared with the placebo group. The two treatment groups did not differ in any other outcome measure. Selegiline was less effective than placebo in reducing symptoms of TD over a 6-week trial. This may be the result of the dopamine agonist effects associated with selegiline.

The delusion of possession in chronically psychotic patients

Sixty-one chronically psychotic outpatients were grouped according to the presence or absence of a history of delusional possession. Compared with patients without a history of delusional possession (N = 36), possessed patients (N = 25) had significantly more self-reported childhood sexual abuse, higher dissociation scores, more cannibis abuse, more experiences of thought control, and more voices heard inside their heads. These findings support the hypothesis that in some psychotic patients, possession beliefs may reflect childhood trauma and dissociation.

Relationship of gender and menstrual status to symptoms and medication side effects in patients with schizophrenia

Schizophrenic outpatients (62 females, 59 males) were evaluated to examine the relationships between menstrual status, gender, clinical measures of psychopathology and drug side effects. Menstrual status was determined for 55 female patients. Blood from 44 female subjects, drawn before the AM dose of neuroleptic, was assayed for prolactin concentrations. In 27 premenopausal women (age < 45 years), six (22%) reported irregular menses and one (4%) reported amenorrhea. Women with irregular menses did not differ in their prolactin levels or neuroleptic dose, from women with regular menses. Amenorrheic women (n = 22) were significantly older than men (n = 59) and menstruating women (n = 33). After controlling for age, menstruating women did not differ in clinical measures of psychopathology, drug side effects, or neuroleptic dose compared to amenorrheic women or men. Comparison of 15 age-matched pairs of menstruating females and amenorrheic females revealed significantly lower levels of akathisia and depression in the menstruating group and a trend towards lower serum prolactin concentrations (P = 0.08). In female subjects, prolactin levels correlated significantly with neuroleptic dose (r = 0.36, P < 0.005). Our results only partially support hypothesized relationships between menstrual status, prolactin levels and neuroleptic effects and serve to emphasize the importance of controlling for age when comparing these clinical variables.