Partial Dopamine Agonist Research Articles

Aripiprazol

We report a case-series of seven patients with a medical history of at least two years of tic disorder treated with the partial dopamine agonist aripiprazole to illustrate its efficacy as a treatment alternative for motor and vocal tics in children and adolescents. A case series of five patients with Tourette Syndrome (TS) and two with chronic motor tic disorder (age range 8; 7-18; 1 year), the majority of whom had been refractory to treatment with other neuroleptics or had ceased treatment due to intolerable side effects, were treated for eight weeks with aripiprazole. Before and after treatment, parents rated the severity of motor and vocal tic symptoms on the Yale Tourette Syndrome Checklist. Within eight weeks mean motor tic symptoms decreased by 66% and mean vocal tic symptoms decreased by 26%. Mean effective dosage was 14.3 mg/day (min. 5 mg, max. 30 mg). Symptoms of comorbid ADHD or Obsessive Compulsive Disorder were not significantly influenced. During medication only mild side effects were observed, e.g., abdominal pain, fatigue and increased emotional sensitivity. No patient dropped out of treatment due to side effects. Aripiprazole may be an effective pharmacologic treatment alternative for individuals with chronic motor tic disorder and TS. It induces quick, significant and sustained effects with few generally mild and transient side effects, if anything. Its effectiveness, especially relative to comorbidities, should be verified in double-blind, placebo-controlled studies.

Evaluation of the efficacy and safety of terguride in patients with fibromyalgia syndrome: Results of a twelve‐week, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group study

To assess the efficacy and safety of terguride, a partial dopamine agonist, in patients with fibromyalgia syndrome (FMS). In a 12-week, multicenter, double-blind, placebo-controlled, parallel-group study, 99 patients were randomized at a ratio of 2 to 1 to receive terguride or placebo. Over 21 days, the dosage was titrated to a maximum daily dose of 3 mg of terguride or placebo, and this fixed dosage was continued over 9 weeks. The primary efficacy variable was the intensity of pain (100-mm visual analog scale). Secondary efficacy variables included the Fibromyalgia Impact Questionnaire (FIQ) score, the tender point score (TPS), and the Hamilton Depression Scale (HDS) score. During the study, patients were evaluated for the presence of cervical spine stenosis by magnetic resonance imaging (MRI). No significant differences in the change in pain intensity, FIQ score, TPS, or HDS score between baseline and 12 weeks were observed in the terguride group as compared with the placebo group. Cervical spine stenosis was detected in 22% of the patients. Only patients with cervical spine stenosis responded to terguride treatment. FIQ scores improved significantly (per-protocol analysis), and pain intensity, the TPS score, and the HDS score showed a trend toward improvement in the terguride group as compared with the placebo group. Terguride treatment was safe. Only those adverse events already known to be side effects of terguride were observed. Premature termination of the study in patients receiving terguride (26%) occurred predominantly during up-titration and in the absence of comedication for treatment of nausea. Terguride treatment did not improve pain, the FIQ score, the TPS, or the HDS score in the total study population. However, a subgroup of patients with cervical spine stenosis seemed to benefit from terguride treatment.

The effect of dopamine partial agonists on the nicotine dependency in patients with schizophrenia

We compared the effects of haloperidol and three atypical antipsychotics (risperidone, olanzapine, and aripiprazole) on nicotine dependence in schizophrenic patients. One hundred and thirty nine schizophrenic patients, who began using antipsychotic medication, were assessed for severity of nicotine dependence and for cigarette craving at baseline and following 8 weeks of treatment using the Fagerström Tolerance Questionnaire (FTQ) and a Likert-style, seven point, visual-analogue rating scale. Nicotine dependence increased in the haloperidol group, but not in atypical antipsychotics groups. Patients treated with aripiprazole showed a reduction both in nicotine dependence and cigarette craving. The effects of aripiprazole, a partial agonist of the dopamine D2 receptor, may reduce the severity of nicotine dependence in schizophrenic patients.

Aripiprazole-induced behavioural disturbance related to impulse control in a clinical setting

Aripiprazole is a novel antipsychotic with a unique pharmacological profile as a dopamine partial agonist; it is approved by the FDA for treatment of schizophrenia and mood disorders. This new antipsychotic has a low risk of adverse events including extrapyramidal syndrome, prolactin elevation, weight gain, and metabolic changes and is recommended by clinical guidelines as a first-line drug for treatment of schizophrenia. However, previous case reports have shown that administration of aripiprazole could induce mood switching and worsening of psychosis, especially after long-term exposure to other antipsychotics (DeQuardo, 2004; Padala et al. 2007). We report two cases that exhibited unexpected adverse effects after administration of aripiprazole for treatment of bipolar disorder. A 57-yr-old male had his first depressive episode with insomnia, loss of concentration, and suicidal ideas at age 22 yr. He was diagnosed with bipolar I disorder when a manic episode occurred at age 38 yr. Because antidepressants induced rapid mood changes, he was hospitalized 14 times and lost his job at the age of 50. Since his last hospitalization when he was aged 51 yr, his symptoms were relatively stable under a medication regimen of 1000 mg/d lithium carbonate and 600 mg/d carbamazepine. From June 2007, he felt a loss of energy and poor concentration, and he withdrew from social activity. In July 2007, 3 mg/d aripiprazole was started. The following week he reported unusual sexual desire and a strong urge to masturbate, although he was still in a depressive state and showed no other manic symptom. One week after stopping aripiprazole, the hypersexuality disappeared. The depressive phase gradually improved to euthymia by October 2007 without any other change of medication. One year later, in September …

Use of the Leksell Gamma Knife in the Treatment of Prolactinoma Patients

The current treatment of choice for prolactinomas is pharmacologic therapy with dopamine agonists (DA). However, these drugs must be taken long-term or even life-long, and they are unsuccessful in adenoma patients who are resistant to or intolerant of DA. Other options in such patients include surgical treatment or radiosurgery with the Leksell gamma knife (LGK). This non-randomized trial was designed to examine the effectiveness of LGK irradiation in treating prolactinoma patients who were resistant to or intolerant of DA. A secondary aim was to investigate the effect of LGK in improving the effects of DA on the size of adenomas, shortening the length of administration of DA, and normalizing prolactin levels permanently. The study population was comprised of 35 patients with prolactin secreting pituitary adenomas (27 females and 8 males), with an average age of 40.3 years (range: 18-71). Nine of the 35 patients (25.7%) had microprolactinomas and 26 of the 35 (74.3%) had macroprolactinomas. The mean ± SD follow-up period was 75.5 ± 34.4 months. Twenty-five patients (71.4%) received only pharmacologic therapy with DA before LGK and 10 patients (28.6%) underwent pituitary adenoma surgery in addition to DA therapy. LGK irradiation was indicated because of drug intolerance (31.4%), partial or complete DA resistance (45.7%), and attempts to shorten the period of treatment with DA or reduce the dosage (22.9%). Pituitary function was monitored regularly by measuring hormone levels at 6-month intervals. The median central radiation dose was 70 Gy (range: 40-80 Gy) and the median minimal peripheral dose was 34 Gy (range: 20-49 Gy). Normoprolactinemia was achieved in 80% (28/35) of the study patients. This included 37.1% (13/35 patients) who discontinued DA treatment and 42.9% (15/35 patients) who continued DA treatment after irradiation. After discontinuation of DA in the study subjects, the median time for hormonal normalization was 96 months. None of the patients achieving normoprolactinemia with LGK experienced any disease relapse. Only 1 patient (2.5%) experienced further growth of the adenoma after LGK irradiation. These findings suggest that LGK may achieve normoprolactinemia in 80.0% of the patients with pituitary adenomas who fail pharmacological therapy due to resistance to, or intolerance of, DAs and insufficient response to DA before radiation. The absence of relapse after normalization with LGK contrasts with DA therapy which produces a permanent remission in less than 50% of patients after discontinuation.

Tic-Störungen und Tourette-Syndrom in der Lebensspanne

Chronic motor and vocal tics lasting longer than a year are classified as Tourette's syndrome (TS). Tics mostly manifest before the age of 11 years. Boys are affected at a threefold higher rate than girls. Tics are often worst at the age of 14; in 50% of the cases the tic symptoms will remit nearly completely. Severely affected patients often suffer from comorbidities. In childhood and adolescence the most common comorbid condition is attention deficit hyperactivity disorder (ADHD). Obsessive-compulsive behaviour, anxiety and affective disorder might occur in the course of TS. A dysregulation in the dopaminergic neurotransmission in the cortico-striatal-thalamic-cortical circuits (CSTC) might be the underlying neurobiological basis. The psychotropic substances administered for TS treatment largely affect the dopaminergic system. The most commonly used atypical neuroleptics are not approved for TS treatment and are used "off label". Atomoxetine might also improve tics in comorbid ADHD. First results of some case series with the partial dopamine agonist aripiprazole are encouraging.

Glutamate agonist LY404,039 for treating schizophrenia has affinity for the dopamine D2High receptor

The glutamate agonist LY404,039 has been used to treat schizophrenia. Because all currently used antipsychotics act on dopamine receptors, it was decided to examine whether this glutamate agonist also had an affinity for dopamine D2 receptors in vitro. The present data show that LY404,039 inhibited the binding of [3H]domperidone and [3H]+PHNO by 15.5 +/- 1.5% to the high-affinity state, D2(High), of cloned dopamine D2(Long) receptors and rat striatal tissue with dissociation constants of between 8.2 and 12.6 nM. This high-affinity component of LY404,039 on the binding of [3H]domperidone was inhibited by the presence of guanine nucleotide, indicating an agonist action of the drug at D2(High). LY404,039 also stimulated the incorporation of [35S]GTP-gamma-S into D2(Long) receptors (EC50% = 80 +/- 15 nM) over the same range of concentrations as occurred for the inhibition of [3H]domperidone by LY404,039 at D2(High) (IC50%(High) = 50 +/- 10 nM). A possible clinical antipsychotic action of LY404,039 may depend on the combined stimulation of glutamate receptors and a partial dopamine agonist action that would interfere with neurotransmission at D2(High) receptors.

Safety and Tolerability of Pardoprunox, a New Partial Dopamine Agonist, in a Randomized, Controlled Study of Patients with Advanced Parkinson’s Disease

Aims: To investigate the safety and tolerability of pardoprunox (SLV308), a novel partial dopamine agonist, as an adjunct to levodopa in patients with advanced Parkinson’s disease, using two titration schedules. Methods: Patients were randomized to pardoprunox (n = 51) or placebo (n = 11). Pardoprunox was titrated to the highest tolerated dose (range, 0.3–42 mg/day) over 7 weeks, using a gradual dose escalation without intermediate steps (group 1) or with intermediate steps (group 2). Results: The cumulative drop-out rate was greater in group 1 (without intermediate steps, 56.0%) than in group 2 (with intermediate steps, 34.6%), or with placebo (9.1%). In group 2, doses up to 18 mg/day were well tolerated with a cumulative drop-out rate of 7.7% (2/26) and a drop-out rate due to adverse events of 4.0% (1/26). The most common adverse events reported were nausea, vomiting, headache, and dizziness. There was a trend for reduced OFF time (p = 0.054) in the combined pardoprunox group compared to placebo. Conclusions: The pardoprunox safety and tolerability profile as an adjunct to levodopa was improved using a gradual titration schedule that included intermediate dose steps. Using this titration, doses up to 18 mg/day were well tolerated.

The relationship between subjective well-being and dopamine D2 receptors in patients treated with a dopamine partial agonist and full antagonist antipsychotics

Antipsychotic drugs produce unpleasant subjective experiences, which have been associated with high levels of dopamine D2 receptor occupancy. Aripiprazole is a partial agonist antipsychotic, which is hypothesized to produce a different subjective experience profile compared to standard D2 antagonist antipsychotics. The aim of this study was to compare the effect of D2 occupancy produced by a partial agonist antipsychotic (aripiprazole) to that of antagonist antipsychotics (risperidone or olanzapine) on the subjective well-being of patients. Subjective well-being was measured using the Subjective Well-being under Neuroleptics Scale (SWN) and was related to dopamine D2 receptor occupancy using [11C]raclopride PET. Patients that were switched to aripiprazole showed improvement in their subjective well-being from 79.80 (S.D.=16.08) to 89.90 (S.D.=15.33), an effect that was sustained for 6 months. This sustained improvement was observed despite very high levels of DA D2 occupancy (82-99%), in contrast to the effects of antagonist antipsychotics on subjective well-being.

Olanzapine pamoate - blockbuster or damp squib?

In the past two decades, there has been a small revolution in the treatment of schizophrenia and related psychoses. During the 1990s, new 'atypical' antipsychotics such as clozapine, risperidone, olanzapine and quetiapine were introduced, largely freeing patients of the considerable burden of acute extrapyramidal adverse effects and tardive dyskinesia. In the current decade, we have seen the introduction of a dopamine partial agonist (aripiprazole) and the first atypical depot injection - risperidone long acting injection (RLAI). Olanzapine (as olanzapine pamoate) is the second of the new drugs to be marketed as a long-acting depot. Leslie Citrome, in this journal (1), opined that long-acting olanzapine may be 'an option to consider for a patient who has a history of response to olanzapine but for whom adherence has been difficult' Is depot olanzapine needed? How much is it likely to be used?

Use of aripiprazole in tardive dyskinesia: An open label study of six cases

Aripiprazole, a partial dopamine agonist has been reported to help reduce symptoms of tardive dyskinesia (TD). In a prospective, open label study of a series of cases, we examined the effectiveness of aripiprazole in reducing TD symptoms. Six clinically stable patients with schizophrenia or Schizoaffective disorder and a moderate to severe TD participated in this study. They were systematically cross-titrated from their current medication to aripiprazole and maintained for 16 weeks. The mean extra pyramidal symptom score measured by Abnormal Involuntary Movement Scale (AIMS) improved from a baseline score of 15.8 to final score of 5 (paired t-test; P=0.0009). The severity of psychiatric symptoms remained unchanged. This study supports our hypothesis that clinically stable patients with moderate tardive dyskinesia who are under treatment with other first- or second-generation antipsychotics may benefit from switching to aripiprazole with a reduction of TD symptoms but with out any significant benefit in psychiatric symptoms. The results need to be viewed with caution and not considered as indicative of a viable treatment option for TD as this is an open label study, and a small sample size.

Subjective, cognitive/psychomotor, and physiological effects of aripiprazole in Chinese light and heavy smokers

Background Drug addiction researchers have begun to study dopamine partial agonists as potential therapeutic agents. The partial dopamine D 2 receptor agonist aripiprazole has recently been tested as a treatment for stimulant and alcohol dependence in both animal and clinical studies. Methods A randomized and placebo-controlled pilot clinical study was conducted in a population of Chinese light and heavy smokers to assess the effect of aripiprazole on various responses to smoking. The primary outcomes were subject’s ratings on questionnaires of smoking urge, withdrawal syndromes, and cigarette evaluation. Placebo, 5, and 10 mg aripiprazole were acutely administered in all participants, with administrations at least 7 days apart. Subjective responses to a smoked cigarette, working memory, and attention/psychomotor performance were assessed before and after drug administration in each experimental session. Abstinence-induced smoking urge, withdrawal symptoms, blood pressure, and heart rate were also measured every 45 min after drug administration. Finally, a cue-testing session was carried out 4 h after each drug administration. Results Administration of 10 mg aripiprazole significantly decreased both the subjective response and psychological reward derived from smoking a cigarette in heavy smokers. While neither 5 nor 10 mg aripiprazole significantly decreased abstinence-induced smoking urges or withdrawal symptoms in light and heavy smokers, these doses substantially attenuated drug cue-induced smoking urges in heavy smokers. Aripiprazole did not affect working memory or attention/psychomotor performance. Conclusions Light and heavy smokers responded differently to aripiprazole across various dependent measures. Aripiprazole may potentially affect various subjective responses to smoking in heavy smokers.

The Effect of Terguride in Carbon Tetrachloride–Induced Liver Fibrosis in Rat

Hepatic stellate cells (HSCs) are considered to be of vital importance in the pathogenesis of liver fibrosis. In vitro studies have demonstrated antiproliferative effects of 5-hydroxytryptamine(2) (5-HT(2), serotonin) receptor antagonists upon HSCs. Terguride, recognized as a partial dopamine agonist, also has potent 5-HT(2) receptor antagonist qualities and has been shown to prevent serotonin-induced organ changes and fibrosis in rats. In the current study, the carbon tetrachloride (CCL(4)) hepatic fibrosis rat model was used in combination with daily administration of terguride to evaluate potential preventive effects of a 5-HT(2) receptor antagonist upon liver fibrosis. Forty rats (Sprague-Dawley) were included in the study. Twelve animals received terguride in combination with CCL(4) and 12 animals were given only CCL(4). The remaining 16 animals served as model controls. The extent of fibrosis was evaluated by liver weight, histologic analysis, biochemical analysis, and alpha-smooth muscle actin (alpha-SMA) immunohistochemistry. There were no significant differences in liver weight, hydroxyproline content, serum alanine and aspartate transaminases, serum hyaluronic acid, or alpha-SMA immunostaining between rats treated with terguride in combination with CCL(4) and rats given only CCL(4). All parameters, however, were significantly lower (P < 0.01) in the model controls. Terguride, a potent 5-HT(2) antagonist, did not prevent the development of liver fibrosis in rats given CCL(4).

Aripiprazole Effects on Alcohol Consumption and Subjective Reports in a Clinical Laboratory Paradigm—Possible Influence of Self‐Control

There has been increasing interest in the use of medications that affect the dopamine receptor in the treatment of alcoholism. Aripiprazole has the unique pharmacology of being a partial dopamine agonist serving to stabilize brain dopamine systems in both frontal cortical and subcortical areas. As such, it might act to dampen alcohol reinforcement and craving and/or alter control over alcohol use. The current clinical laboratory study was conducted to evaluate the safety and efficacy of aripiprazole as a potential agent to alter drinking and objective effects of alcohol. Thirty nontreatment seeking alcoholics were enrolled in a subacute human laboratory study and received double-blind treatment with up to 15 mg of aripiprazole (n = 15) or identical placebo (n = 15) for 8 days. Tolerability and utility of aripiprazole was monitored during natural drinking over the first 6 days of medication treatment and also during a free choice limited access alcohol consumption paradigm following an initial drink of alcohol in a bar-lab setting on Day 8. Aripiprazole was well tolerated and reduced drinking in nontreatment seeking alcoholics over 6 days of natural drinking--especially in those with lower self control (more impulsive). It also reduced drinks in the bar-lab after a priming drink and broke the link between priming drink induced stimulation and further drinking. During the bar-lab drinking session, there were no differences in subjective high, intoxication, or craving between subjects treated with aripiprazole or placebo. This study joins several others in demonstrating the utility of subacute dosing laboratory paradigms for evaluating medication effects in alcoholics. Aripiprazole was well tolerated and lowered alcohol use, especially in those with lower impulse control. Further study is needed to determine the safety and utility of aripiprazole in the treatment of alcoholism and if subgroups of alcoholics are more likely to respond.

Time course of the changes in antipsychotic-induced hyperprolactinemia following the switch to aripiprazole

Hyperprolactinemia is an important but neglected adverse effect of antipsychotic medication. All first generation antipsychotics and the second generation antipsychotics amisulpride and risperidone have been shown to cause marked elevation in serum prolactin levels, whereas most other second generation antipsychotics and aripiprazole appear to have little or no effect on serum prolactin levels. This study was aimed to assess the time course of changes in antipsychotic-induced hyperprolactinemia during the process of antipsychotic switching to aripiprazole. Twenty-three female schizophrenic subjects with risperidone- or sulpiride-induced symptomatic hyperprolactinemia were recruited into the study and 20 of them completed the trial. We added aripiprazole to the therapeutic dose first, then overlapped the preexisting antipsychotic treatment and aripiprazole, and finally tapered the preexisting antipsychotic treatment. Clinical status was assessed by using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression Severity Scale (CGI-S). Assessment scales and serum prolactin levels were measured at baseline, during the combination treatment period, and four weeks after having completed discontinuation of the preexisting antipsychotic treatment. Switching antipsychotic drugs to aripiprazole was effective in reducing serum prolactin levels and restoring menstruation in schizophrenic patients who received prolactin-raising antipsychotics. Mean serum prolactin levels at baseline, during combination period, and after the switch were 97.0 ± 69.0 ng/ml, 27.2 ± 10.6 ng/ml ( p < 0.001, vs. baseline), and 12.2 ± 5.3 ng/ml ( p < 0.001, vs. baseline), respectively. None of the study subjects experienced any serious adverse effects during the switching process. No significant changes were noted in the PANSS and CGI-S scores during the switching process. The prolactin-normalizing effects of aripiprazole are likely caused by the unique characteristics of the dopamine partial agonist with its high affinity for dopamine D 2 receptors.

Dopamine D2High receptors moderately elevated by bifeprunox and aripiprazole

Because long-term antipsychotics elicit behavioral dopamine supersensitivity, the present study examined whether 7-9 days administration of partial dopamine D2 agonists with antipsychotic activity, bifeprunox and aripiprazole, could induce biochemical changes that suggest dopamine supersensitivity. In rats, behavioral dopamine supersensitivity is associated with increased dopamine D2(High) receptors in homogenized striata. In control rat striata, bifeprunox and aripiprazole had similar K(i) values at D2 receptors. In human cloned D2Long receptors, however, aripiprazole had a K(i) of 9.6 nM and recognized 41% of the D2 receptors to be in the D2(High) state, while the values for bifeprunox were 1.3 nM and 69%, indicating that bifeprunox had higher potency and efficacy at D2. Nine days of subcutaneously injected bifeprunox (0.25 mg/kg/day) and 7 days of aripiprazole (1.5 mg/kg) increased D2(High) receptors by 102-129% and 108-188%, respectively, although the total population of D2 receptors revealed no significant changes. The increase in D2(high) receptors induced by dopamine D2 partial agonists appear to be of smaller magnitude than those seen previously with D2 antagonist antipsychotics. Future research needs to test directly whether long-term treatment with dopamine partial agonists leads to any behavioral dopamine supersensitivity.

A Multiple-Center, Randomized, Double-Blind, Placebo-Controlled Study of Oral Aripiprazole for Treatment of Adolescents With Schizophrenia

Aripiprazole is a dopamine partial agonist approved for use in adults for short- and long-term treatment of schizophrenia and bipolar disorder. This study was designed to examine the acute efficacy, safety, and tolerability of aripiprazole for adolescents with schizophrenia. This was a 6-week multicenter, double-blind, randomized, placebo-controlled trial. Subjects 13 to 17 years old with a DSM-IV diagnosis of schizophrenia and a Positive and Negative Syndrome Scale (PANSS) total score of 70 or more were randomly assigned (1:1:1 ratio) to placebo or 10 or 30 mg/day of aripiprazole. The primary endpoint was mean change from baseline to endpoint (last observation carried forward) in PANSS total score. Assessments of safety and tolerability included spontaneously reported adverse events, extrapyramidal symptom scores, serum prolactin concentration, body weight, and metabolic measures. Of 302 patients, 85% completed the 6-week study. The mean baseline PANSS score was 94.1. At the end of the study, both aripiprazole doses showed statistically significant differences from placebo in reduction in PANSS total score. Adverse events occurring in more than 5% of either aripiprazole group and with a combined incidence at least twice the rate for placebo were extrapyramidal disorder, somnolence, and tremor. Mean changes in prolactin were -8.45, -11.93, and -15.14 ng/ml for placebo and 10 mg and 30 mg of aripirazole, respectively. Mean body weight changes were -0.8, 0.0, and 0.2 kg for placebo and 10 mg and 30 mg of aripiprazole, respectively. Both 10- and 30-mg/day doses of aripiprazole were superior to placebo in the acute treatment of adolescents with schizophrenia. Aripiprazole was generally well tolerated.

Aripiprazole Effects on Psychosis and Chorea in a Patient With Huntington’s Disease

Back to table of contents Previous article Next article Letters to the EditorFull AccessAripiprazole Effects on Psychosis and Chorea in a Patient With Huntington’s DiseaseWEI-CHEN LIN M.D.YUAN-HWA CHOU M.D., Ph.D.,WEI-CHEN LIN M.D.Search for more papers by this authorYUAN-HWA CHOU M.D., Ph.D.Search for more papers by this author,Published Online:1 Sep 2008https://doi.org/10.1176/appi.ajp.2008.08040503AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Huntington’s disease is an autosomal dominant inherited disorder characterized by a triad of motor, cognitive, and psychopathological symptoms (1) . Currently, the only treatment options available for the disease are symptomatic. Aripiprazole is a novel antipsychotic drug that possesses the pharmacological characteristics of a partial agonist of the dopamine D 2 and serotonin 5-HT 1A receptors and antagonist of the 5-HT 2A receptor. We report the use of aripiprazole in the treatment of psychotic symptoms in a patient with Huntington’s disease whose diagnosis was confirmed by DNA analysis. “Mr. A” was a 47-year-old single man who suffered from frequent falls as a result of an unsteady gait and involuntary movements over the past 4 years. He was diagnosed with Huntington’s disease but refused treatment. Approximately 2 years before his current evaluation, he began to demonstrate impairment in activities of daily living and talking to himself. He also developed irritability, persecutory delusions, and intermittent violent behavior toward his family. Obvious choreiform movements and unsteady gait were noted when the patient was admitted to the acute psychiatric ward. His family history was positive for Huntington’s disease, with an elder brother who was bedridden and a sister who died from the disease. His medical history showed that he had only received irregular treatment with risperidone orally (1–3 mg per day) during a 2-week period. Aripiprazole (10 mg per day) was started and increased to 20 mg per day. Subsequently, his personal hygiene and psychotic symptoms were significantly improved within 2 weeks. His choreiform movement decreased significantly, and his gait became stable, enabling him to walk smoothly without assistance. Before treatment with aripiprazole, his score on the chorea sub-item of the Unified Huntington’s Disease Rating Scale was 18. After treatment, his score decreased to 8. The pathophysiology of involuntary movements among individuals with Huntington’s disease may be related to the dopamine system (2) , although the genetic defect with aberrant cytosine-adenine-guanine trinucleotide repeats in the ITI5 gene on the short arm of chromosome 4 implicates dysfunction of the glutamate system. Interestingly, in an animal model it has been shown that a dopamine partial agonist could partially restore social withdrawal behavior in hypoglutamatergic mice (3) , which implicates the interaction of dopamine and glutamate systems. Aripiprazole, which has unique dopamine receptor activity compared with other atypical antipsychotics, may similarly have unique effects in treating the psychotic symptoms of Huntington’s disease. Future controlled studies may help provide an understanding of the role of various neuroleptics in the treatment of psychotic symptoms associated with Huntington’s disease. Taipei, TaiwanThe authors report no competing interests.This letter (doi: 10.1176/appi.ajp.2008.08040503) was accepted for publication in May 2008.Reprints are not available; however, Letters to the Editor can be downloaded at http://ajp.psychiatryonline.org.

Partial Dopamine Agonist Beneficial in Early Parkinson's

Partial Dopamine Agonist Beneficial in Early Parkinson's

Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High receptors: D2 basis for schizophrenia

It has previously been reported that the glutamate ionotropic antagonist phencyclidine directly inhibits the release of prolactin in anterior pituitary cells in culture, suggesting that phencyclidine has a dopamine (DA)-like action on prolactin-releasing cells. It has also been reported that the glutamate metabotropic agonist LY379268 can stimulate the incorporation of [35S]GTP-gamma-S into DA D2Long receptors. The present study was done to examine whether such glutamatergic drugs had similar actions on the DA D2Short receptor. The present results show that phencyclidine, ketamine, and LY379268 also stimulated the incorporation of [35S]GTP-gamma-S into D2Short receptors. The proportion of D2Long and D2Short receptors existing in the high-affinity state were both markedly reduced by NaCl. While phencyclidine and LY379268 each stimulated the incorporation of GTP-gamma-S into D2Long and D2Short receptors, this stimulation was reduced by NaCl, with D2Short being much more sensitive than D2Long to the inhibition by NaCl. The binding of phencyclidine and LY379268 to D2High receptors in vivo was directly confirmed by the i.v. injection of phencyclidine and LY379268 in which 50% inhibited the binding of [3H]PHNO to the striatum ex vivo at 0.25 and 1.5 mg/kg, respectively. The results confirm that glutamate agonists and antagonists have a significant affinity for DA D2High receptors. The psychotogenic action of phencyclidine may stem from a combination or synergistic action of glutamate receptor antagonism and DA D2 agonism. In addition, the antipsychotic clinical action of LY379268 congeners such as LY404039 may be related to a combined or synergistic action of glutamate receptor stimulation together with a partial DA agonist action that reduces endogenous DA neurotransmission.