Gerald A. Maguire

Increased dopamine activity associated with stuttering

POSITRON emission tomography using 6-FDOPA as a marker of presynaptic dopaminergic activity was used to investigate the role of the dopamine system in stuttering. Three patients with moderate to severe developmental stuttering were compared with six normal controls. Stuttering subjects showed significantly higher 6-FDOPA uptake than normal controls in medial pre-frontal cortex, deep orbital cortex, insular cortex, extended amygdala, auditory cortex and caudate tail. Elevated 6-FDOPA uptake in ventral limbic cortical and subcortical regions is compatible with the hypothesis that stuttering is associated with an overactive pre-synaptic dopamine system in brain regions that modulate verbalization.

A positron emission tomography [18F]deoxyglucose study of developmental stuttering.

Positron emission tomography using [18F]deoxyglucose (FDG) as a marker of regional brain metabolism was used to investigate the neural substrate of stuttering. Four patients with severe developmental stuttering were studied while reading aloud to another person (stuttering condition) and while reading aloud in unison with someone else (non-stuttering condition). The patients were also compared with four normal controls reading aloud by themselves. In the stuttering condition, significant decreases in regional glucose metabolism in Brocas area, Wernickes area and frontal pole were seen compared with themselves while not stuttering. These differences were also seen in stuttering condition compared with normal controls. Significantly lower left caudate metabolism was seen in patients during both stuttering and non-stuttering conditions compared with normal controls. A circuit for stuttering is proposed based on these findings.

Improvement in hyperprolactinemia and reproductive comorbidities in patients with schizophrenia switched from conventional antipsychotics or risperidone to olanzapine

This open-label, prospective, 4-month study in hyperprolactinemic patients with schizophrenia explored whether prolactin levels decrease after switching antipsychotic therapy to olanzapine. A secondary objective was to determine if reproductive morbidities and sexual dysfunction occurring with hyperprolactinemia improved with prolactin normalization. Clinically stable patients with schizophrenia, who had hyperprolactinemia defined as >18.8 ng/ml for males and >24.2 ng/ml for females, were randomized to: remain on current therapy (n=27) or switch to olanzapine, 5-20 mg/day, (n=27). Baseline prolactin levels in female patients randomized to receive olanzapine (n=14) were 66.3+/-38.7 ng/ml and were 82.0+/-37.6 (p=.32) in those remaining on their pre-study antipsychotic medication (n=14). In male patients, baseline prolactin levels were 33.7+/-12.1 and 33.5+/-13.8 ng/ml (p=.97), respectively, for those randomized to olanzapine (n=13) or remaining on pre-study treatment (n=13). At study end, patients switched to olanzapine experienced significant reductions in mean serum prolactin levels of 19.8+/-18.1 ng/ml in males (p=.02), and 32.3+/-47.5 ng/ml in females (p=.01), but prolactin continued to be elevated in patients who remained on pre-study antipsychotic treatment. After switching to olanzapine treatment, male patients experienced significantly (p=.03) increased free testosterone levels but there were no significant improvements in total testosterone levels; some female patients experienced improved menstrual cycling, as well as resolution of galactorrhea and gynecomastia, and sexual functioning was significantly improved in both genders. Patients switched to olanzapine, as well as those remaining on their pre-study medication, maintained clinical stability, their symptoms continued to improve, although there were no significant between-treatment differences in improvement. Treatment-emergent adverse events did occur in both treatment groups; however, they were not significantly different between groups. Olanzapine-treated patients experienced significantly lower eosinophil counts and higher elevations in low-density lipoproteins and standing blood pressure than non-switched patients. Olanzapine treatment may offer sustained reduction in serum prolactin and improvement in sexual and reproductive comorbid symptoms in patients with schizophrenia who have treatment-emergent hyperprolactinemia.

Effectiveness of rapid initial dose escalation of up to forty milligrams per day of oral olanzapine in acute agitation.

Background Patients experiencing an acute decompensation of schizophrenia or bipolar disorder often present in an agitated state. Agitation presents a barrier to therapy, interrupting the typical physician-patient alliance and creating a disruptive, even hazardous, environment. Rapid assessment and effective treatment are necessary to manage agitation and, potentially, to shorten the time to recovery. Methods One hundred forty-eight acutely agitated patients received either: rapid initial dose escalation (RIDE) in which up to 40 mg of oral olanzapine was allowed on days 1 and 2, up to 30 mg on days 3 and 4, and 5 to 20 mg thereafter; or usual clinical practice (UCP) in which patients received 10 mg/d olanzapine plus up to 4 mg lorazepam on days 1 and 2, up to 2 mg on days 3 and 4, and olanzapine 5 to 20 mg/d thereafter. The Positive and Negative Syndrome Scale-Excited Component (PANSS-EC: poor impulse control, tension, hostility, uncooperativeness, and excitement) measured at 24 hours was the primary measure. Secondary assessments of agitation and safety were also performed. Results Agitation improved significantly from baseline for both treatment groups; however, improvement with the RIDE strategy was superior to UCP. The RIDE group improvement was superior on the primary efficacy measure (PANSS-Excited) at 24 hours; it was superior on all agitation measures at the end of double-blind treatment. Both treatments were well tolerated, with no clinically significant differences in safety measures. Treatment was not limited by oversedation and attention improved from baseline in both groups. Conclusions This study demonstrates the value of olanzapine in the treatment of acutely agitated patients. A new approach to olanzapine dosing that expands the initial dose range up to 40 mg/d may offer superior efficacy in rapidly and effectively controlling the symptoms of agitation.

Risperidone for the treatment of stuttering.

A randomized, double-blind, placebo-controlled study was conducted to assess the efficacy of risperidone in the treatment of developmental stuttering in 16 adults. Eight subjects received placebo and eight received risperidone at 0.5 mg once daily at night, increased to a maximum of 2 mg/day. After 6 weeks of treatment, decreases in all measures of stuttering severity were greater in the risperidone group than in the placebo group; the between-treatment difference was significant (p < 0.05) on the most important measure, the percentage of syllables stuttered. In the risperidone group, reductions from baseline in scores for the percentage of syllables stuttered, time stuttering as a percentage of total time speaking, and overall stuttering severity were significant (p < 0.01); changes in scores on the fourth measure of stuttering, duration, were not significant. No significant decreases occurred in the placebo group. Among the eight patients in the risperidone group, five responded best to 0.5 mg/day, with stuttering recurring at higher doses. The remaining three patients responded better with increasing doses of risperidone. Risperidone was generally well tolerated. The results of this small study indicate that risperidone may be effective in the treatment of developmental stuttering. This finding needs to be confirmed in a larger trial.

Management of Child and Adolescent Stuttering with Olanzapine: Three Case Reports

Vast arrays of medications have been used, with limited success, to manage stuttering. Haloperidol and risperidone are the only two medications that have shown efficacy via double-blind studies in controlling stuttering symptoms. We present the first case reports of olanzapine in the management of stuttering. Three case histories are presented: a 10-year-old boy, a 16-year-old male adolescent with developmental stuttering, and a 9-year-old boy with medication-induced stuttering whose symptoms are successfully controlled with olanzapine. These case studies suggest that olanzapine may be a pharmacologic option in the management of stuttering.

Alleviating stuttering with pharmacological interventions.

Stuttering is a speech disorder characterised by frequent prolongations, repetitions or blocks of spoken sounds and/or syllables. Stuttering is very common and is classified by the Diagnostic and Statistical Manual of Mental Disorders – Fourth Edition (DSM-IV) as an Axis I disorder. In spite of this, stuttering treatment is sporadically addressed by a practicing physician, especially in the US. Much has recently been learned of the neurophysiological basis of this disorder, which has provided insight into novel treatment strategies, thus helping to guide the practising clinician. Stuttering is likely to be associated, at least in part, to dopamine hyperactivity in the brain. Novel dopamine antagonists such as risperidone and olanzapine, have recently been shown to improve the symptoms of stuttering providing a strong foundation for physicians to more effectively treat this disorder.

Exploratory randomized clinical study of pagoclone in persistent developmental stuttering: the EXamining Pagoclone for peRsistent dEvelopmental Stuttering Study.

Introduction: Stuttering is a speech disorder in which the flow of speech is disrupted by repetitions, prolongation, and blocks of sounds, syllables, or words. No pharmacological treatments are approved for use in stuttering, and the most common form of treatment is speech therapy. This study was designed to assess the safety, tolerability, and effectiveness of pagoclone during 8 weeks of double-blind treatment followed by a 1-year open-label extension in patients who stutter. Methods: An 8-week, multicenter, parallel-group, 2-arm, randomized (ratio 2:1 pagoclone-placebo), double-blind study with a 1-year open-label extension conducted at 16 US centers, including men and women aged 18 to 65 years who developed stuttering before 8 years of age. Twice-daily dosing with pagoclone (n = 88 patients) or matching placebo (n = 44 patients), with primary and secondary efficacy variables defined a priori, including Stuttering Severity Instrument Version 3 outcomes, clinician global impressions of improvement, and the change in the percentage of syllables stuttered. Results: Pagoclone produced an average 19.4% reduction in percentage of syllables stuttered compared with 5.1% reduction for placebo. During open-label treatment, a 40% reduction in the percent syllables stuttered was observed after 1 year of treatment with pagoclone. The most commonly reported adverse event during double-blind treatment was headache (12.5% pagoclone patients, 6.8% placebo patients). Discussion: Pagoclone was effective in reducing symptoms of stuttering and was well tolerated. In light of its favorable tolerability profile, as well as consistency of effects across multiple efficacy variables, pagoclone may have potential as a pharmacological treatment of stuttering. Limitations: The main limitation of this study was the adequacy of the number of subjects who participated because this study was conducted as a pilot investigation. Furthermore, as this condition waxes and wanes, the assessment of stuttering within the clinic setting may not be an adequate reflection of the stuttering of the patients within the community.

A randomized controlled trial of the effect of sublingual orally disintegrating olanzapine versus oral olanzapine on body mass index: The PLATYPUS Study

BACKGROUND Patients with schizophrenia and bipolar disorder have frequently reported weight gain during olanzapine treatment. Previous studies have observed a decrease in weight gain, or weight loss, in patients switching from standard olanzapine tablets (SOT) to orally disintegrating olanzapine (ODO) tablets. The primary objective of this study was to investigate the change in body mass index (BMI) in patients who had previously gained weight with SOT and continued with this therapy during the study period, compared with those patients who switched to ODO during the study period. METHODS This was a 16-week, multicentre, randomized, double-blind, double-dummy, study of outpatients diagnosed with schizophrenia, schizoaffective disorder, related psychotic disorder or bipolar disorder, who were taking 5-20 mg SOT daily. Patients continued treatment with 5-20 mg olanzapine in a flexible single daily dose, and were randomized to either receive sublingual ODO plus an oral placebo, or sublingual placebo plus SOT. RESULTS No statistically significant between group differences in mean change from baseline in BMI, weight or waist circumference were observed. Analysis of change in body weight from baseline, by pre-specified category (no change, loss of >or=1.5 kg, gain of >or=1.5 kg), revealed a significant difference between groups, favoring ODO patients, who also experienced a significant reduction in subjective appetite and better treatment compliance, compared to patients in the SOT group. CONCLUSIONS In this study, patients treated with ODO experienced a similar mean change in BMI and weight from baseline, to those patients treated with SOT.

Stuttering: Neuropsychiatric features measured by content analysis of speech and the effect of risperidone on stuttering severity

Positron-emission tomographic (PET) studies and genetic research of stuttering have recently revealed underlying cerebral neurobiologic contributing factors in this disorder. We aimed to assess whether cognitive impairment and other neuropsychiatric dimensions could be detected through computerized content analysis of short samples of speech from stutterers, and whether administration of risperidone in a double-blind placebo-controlled study could decrease the severity of stuttering, as well as any of the neuropsychiatric features of these stutterers. A group of 21 stutterers with the developmental form of stuttering, an onset before age of 6 years, aged 20 to 74 years, and who were otherwise free of major medical or psychiatric problems, initially gave a 5-minute tape-recorded speech sample in response to purposely ambiguous instructions to talk about any interesting or dramatic life experiences. Then, half of these subjects (n = 10) were randomly selected to receive 6 weeks of risperidone treatment up to 2.0 mg/d and the other half (n = 11) were administered a placebo. Both groups of subjects gave a second verbal sample after 6 weeks of treatment. Significantly elevated cognitive impairment and social alienation-personal disorganization scores, derived from the computerized content of the initial 5-minute speech samples, were found. After 6 weeks, the risperidone group improved significantly on a measure of severity of stuttering but did not improve on the percentage of time spent stuttering. The placebo group did not improve on either measure of stuttering. The psychopathological processes of subjects who received risperidone treatment, including those with elevated cognitive impairment and social alienation-personal disorganization, did not change significantly. However, stutterers who had lower scores on verbal content analysis-derived shame anxiety, guilt anxiety, or hostility inward measures improved significantly more with risperidone than stutterers with higher scores on these measures. The findings of elevated cognitive impairment and social alienation-personal disorganization scores of adult stutterers with the early developmental form of stuttering are consistent with the neurobiologic abnormalities found in PET-scan and genetic research involving stutterers. Risperidone (< or =2.0 mg/d) can reduce the severity of stuttering while not significantly affecting the magnitude of neuropsychiatric dimensions such as cognitive impairment or social alienation-personal disorganization. The less the inward shame, guilt, or hostility of the stutterers, the better the beneficial effect of risperidone on the severity of stuttering.