Dopamine Antagonist Properties Research Articles

Hyperprolactinemia With Aripiprazole

Aripiprazole, due to its partial agonist activity at the D2 receptors, is often recommended as the drug of choice in patients who develop antipsychotic-induced hyperprolactinemia. We report a case of a female patient who developed hyperprolactinemia while on treatment with aripiprazole. This partial D2 agonistic activity of aripiprazole could be dose related, and hence, at higher doses, aripiprazole by itself can have dopamine antagonistic properties and hence cause prolactin system abnormalities.

Psychotic exacerbation and emotional dampening in the daily life of patients with schizophrenia switched to aripiprazole therapy: a collection of standardized case reports

Blockade of the dopamine D2 receptor is a key mechanism in the antipsychotic treatment of patients with a psychotic disorder, but may also induce emotional deficits. The partial D2 agonistic profile of aripiprazole has, therefore, been suggested to favor emotional wellbeing compared with the pure dopamine antagonistic properties of traditional antipsychotics. The current study used the experience sampling method (a structured diary technique) to assess the effects of switching from treatment with traditional dopamine antagonist antipsychotics to treatment with the partial dopamine agonist aripiprazole on emotional wellbeing in the daily life of 13 patients with a diagnosis of schizophrenia. More than half of all patients experienced exacerbation of psychotic symptoms after they had switched to the aripiprazole medication regime, consequently resulting in dropout of the study. Furthermore, switching to aripiprazole treatment, when effective in terms of symptom reduction, was accompanied by decreased feelings of both positive and negative affect in daily life, suggestive of a general state of emotional dampening. Although the scale of the current study and the 54% dropout rate call for careful interpretation of the data, implementation of ecological monitoring in psychopharmacological research may open up new avenues for untangling the working mechanisms of compounds with regard to their impact on mental states.

261 Iloperidone (fanapt), a novel atypical antipsychotic, is a potent HERG blocker and delays cardiac ventricular repolarization at clinically relevant concentration

Iloperidone is a second-generation antipsychotic that was approved on May 6, 2009 by the FDA for treating schizophrenia in adults. It is a piperidinyl-benzisoxasole derivative with mixed dopamine (D2) and serotonin (5-HT2A) antagonist properties. Interestingly, as specified in the product labelling, numerous cases of dose-dependent QT interval prolongation have been reported with iloperidone. Our aims were therefore to evaluate the effects of iloperidone on cardiac ventricular repolarization.

Comparative pharmacokinetics and bioequivalence of two tablet formulations of 2 mg risperidone in healthy Thai male volunteers

Risperidone is an atypical antipsychotic drug with potent serotonin and moderate dopamine antagonistic properties. It possesses good bioavailability following oral administration. Risperidone is primarily converted by the cytochrome P450 2D6 (CYP2D6) and 3A4 (CYP3A4) enzymes to 9-hydroxyrisperidone, its active metabolite with equivalent potency to the parent compound. This study aimed to compare the pharmacokinetics and determine bioequivalence of two risperidone immediate release oral tablets, a test formulation (Risperidone GPO® or "Test") and a reference formulation (Risperdal® or "Reference"). A single-dose, randomized, fasting, 2-period, 2-sequence, crossover study design with a 2-week washout period was conducted in 23 healthy Thai male volunteers. Blood samples were collected predose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72 and 96 h following an oral administration of 2 mg risperidone. The plasma concentrations of risperidone and 9-hydroxyrisperidone were determined by using a validated HPLC method. Pharmacokinetic parameters of Test and Reference were obtained by noncompartmental analysis. The 90% confidence intervals for Test/Reference ratios of the pharmacokinetic parameters (Cmax, AUC0-t and AUC0-∞) of both risperidone and its active metabolite (9-hydroxyrisperidone) fell within the acceptable bioequivalence range (80 - 125%) according to ASEAN guideline. The two risperidone formulations are bioequivalent. The test formulation may be used for generic substitution where applicable.

Iloperidone for the Management of Adults with Schizophrenia

Background Iloperidone is a second-generation antipsychotic drug approved in May 2009 by the US Food and Drug Administration (FDA) for the acute treatment of schizophrenia in adults. It is a piperidinyl-benzisoxazole derivative with mixed serotonin (5HT2A) and D2 dopamine antagonist properties. Objective The purpose of this article was to review the pharmacology, pharmacokinetics, efficacy, safety, and role in treatment for iloperidone in schizophrenia. Methods Scientific and clinical data were collected through searches of PubMed, ClinicalTrials.gov, International Pharmaceutical Abstracts, and the FDA, using the search term iloperidone, and limited to English-language articles. Reference lists were reviewed for additional publications. Dates included the beginning of the database through 2010. No limits were placed on study design. Results In a 4-week Phase III trial, iloperidone 12 mg twice daily lowered the Positive and Negative Syndrome Scale (PANSS) total scores to a significantly greater extent than did placebo (−12 vs −7.1; P < 0.01). The ziprasidone active control also separated from placebo (−12.3 vs −7.1; P < 0.05). A pooled analysis of 3 Phase III trials compared iloperidone in divided doses to placebo. The primary outcome was reduction in PANSS scores. Study 1 included iloperidone 4, 8, or 12 mg/d, haloperidol as an active control, and placebo. The PANSS reduction in the 12 mg/d group was significantly greater at end point versus baseline when compared with placebo (−9.9 vs −4.6; P = 0.047). Study 2 included iloperidone 4 to 8 mg/d or 10 to 16 mg/d, risperidone 4 to 8 mg/d, or placebo. The primary efficacy measure was change from baseline to end point in the Brief Psychiatric Rating Scale (BPRS). Improvement from baseline on all iloperidone doses was significantly greater than with placebo (4–8 mg/d group: −6.2, P = 0.012; 10–16 mg/d group: −7.2, P = 0.001; placebo, −2.5). Study 3 included iloperidone 12 to 16 mg/d, risperidone 6 to 8 mg/d, and placebo. The results on the primary efficacy variable, reduction in the BPRS score, was not significant for the 12 to 16 mg/d group versus placebo (−7.1 vs −5.0; P = 0.09), but was significant for the 20 to 24 mg/d iloperidone group (−8.6 vs −5.0; P = 0.01) and for the risperidone group (−11.5 vs 5.0; P < 0.001). A 52-week maintenance trial included iloperidone versus haloperidol as an active control. The primary efficacy variable was time to relapse. Comparison of mean time to relapse of the 2 arms showed no significant difference. The most common adverse events (AEs) associated with iloperidone were dizziness (5.1%–23.2%), dry mouth (5.2%–10.4%), somnolence (4%–13%), and dyspepsia (4.8%–7.8%). AEs appeared dose related. Prescribing information recommends a starting dosage of 1 mg twice daily and then titrated over 7 days to reach a target dosage of 12 to 24 mg/d. The titration is necessary to reduce the risk of orthostatic hypotension-related dizziness. Conclusions Data support that when titrated slowly to a therapeutic dosage, iloperidone is generally well tolerated, has a favorable safety profile, and is an effective treatment option in patients with schizophrenia. Its place in therapy and performance in a typical patient population remain to be established. Slow initial titration and twice-daily dosing are potential disadvantages.

Phenothiazines interfere with dopaminergic neurodegeneration in Caenorhabditis elegans models of Parkinson's disease

Oxidative stress is involved in the pathogenesis of various neurodegenerative disorders, conventional antioxidant strategies have yet been of limited success. We have employed transgenic Caenorhabditis elegans expressing DsRed2 in dopaminergic neurons and CFP pan-neuronally, to characterize in larval and adult animals the effects of rotenone and 1-methyl-4-phenyl-pyridinium (MPP +) on the dopaminergic system. Investigating the antioxidant phenothiazine and different derived antipsychotic drugs, it was found that free phenothiazine exerted strong neuroprotection at the cellular level and resulted in a better performance in behavioral assays, whereas apomorphine and other dopamine agonists only rescued adult locomotor parameters. Phenothiazine antipsychotics with dopamine antagonist properties were likewise not cytoprotective, but even induced motor deficits by themselves. Beyond phenothiazine, other tricyclic imines elicited significant neuroprotection at considerably lower doses than different natural antioxidants. Mitochondrially targeted antioxidants were more potent than these untargeted natural antioxidants, yet not as potent as the untargeted compound phenothiazine. Thus, dopaminergic toxicity of rotenone and MPP + in vivo can be forestalled by nanomolar concentrations of certain chain-breaking antioxidants irrespective of dopamine receptor modulation or mitochondrial targeting.

Effects of Atypical Antipsychotic Drugs on Intralipid Intake and Cocaine-Induced Hyperactivity in Rats

Clozapine and olanzapine have been shown to acutely stimulate consumption of a fat emulsion (Intralipid) by male Lister hooded rats. We initially investigated the extent of any sex difference in Intralipid hyperphagia associated with olanzapine treatment. We then examined the degree of Intralipid hyperphagia produced by a range of atypical antipsychotic drugs having different associations with human weight gain, and also determined their effects on cocaine-stimulated locomotor activity as a measure of functional dopamine antagonism in vivo. Olanzapine (0.1-1 mg/kg) stimulated Intralipid intake to an equal extent in male and female rats. Quetiapine (10 mg/kg) also stimulated Intralipid intake whereas ziprasidone (0.3-10 mg/kg) or risperidone (0.03-0.3 mg/kg) did not have this effect. All of the compounds, except quetiapine, reduced cocaine-stimulated locomotor activity but the relationship to the degree of Intralipid hyperphagia was variable. Since there was a positive relationship between Intralipid hyperphagia and the reported extent of human body weight gain, we conclude that Intralipid hyperphagia may have predictive value for this drug-associated side effect and is not related to the dopamine antagonist properties of these agents.

Treatment with medications affecting dopaminergic and serotonergic mechanisms: Effects on fluency and anxiety in persons who stutter

Medications with dopamine antagonist properties, such as haloperidol, and those with serotonin reuptake inhibitor properties, such as clomipramine, have been shown to improve fluency. To examine the degree to which each of these two pharmacological mechanisms might independently affect fluency, a selective serotonin reuptake inhibitor, paroxetine, and a selective dopamine (D-2) antagonist, pimozide, were evaluated. Both types of medications also affect mood and anxiety, factors that could influence fluency levels. Therefore, we also evaluated the medications’ effects on generalized and speech-related anxiety and the relationships between changes in anxiety and changes in fluency in 11 subjects with a history of developmental stuttering. The randomized, double blind, placebo-controlled crossover study that was designed had to be terminated prior to completion due to severe side effects following withdrawal from paroxetine. Even with a reduced sample size ( n = 6), significant improvement in percent fluent speaking time ( p = 0.02) was found using a telephone task between baseline and pimozide ( n = 6), with average duration of dysfluencies significantly shorter ( p = 0.04) but no significant difference in the estimated number of dysfluencies per minute. This significant improvement was associated with non-significant increases in generalized anxiety, but non-significant decreases in speech-related anxiety. No significant differences were found in fluency between baseline and paroxetine ( n = 5). These preliminary results suggest that fluency improvement is more likely to be mediated by dopaminergic rather than serotonergic mechanisms. Due to its side effects, however, pimozide may be considered a risk for treatment of stuttering. Educational objectives: As a result of reading this paper the reader will describe and explain: (1) how medications may affect fluency and the rationale for selecting medications for treatment trials; (2) the interrelationship between fluency and anxiety; and (3) factors important in developing clinical trials using medications.

Effect of Quetiapine in the Treatment of Panic Attacks in Patients with Schizophrenia: 3 Case Reports

The authors describe three schizophrenic patients who suffered from panic attacks and experienced marked improvement of these episodes after switching to quetiapine from their previous antipsychotics (haloperidol, bromperidol, and risperidone), which have high dopamine antagonistic properties such as haloperidol, bromperidol, and risperidone.

Hyperprolactinaemia and antipsychotic therapy in schizophrenia

SUMMARYProlactin is a polypeptide hormone that exists as a number of isoforms and is involved in a multitude of physiological processes. Prolactin secretion is promoted by various physiological stimuli and pathological processes and is inhibited by the action of dopamine on the lactotroph cells of the hypothalamus. Hyperprolactinaemia, an elevation of prolactin levels above the norm, is a physiological occurrence and is not of concern (including sexual dysfunction and decreased bone mineral density). Treatment of hyperprolactinaemia is usually confined to the removal of the primary cause of the disease, but several dopamine agonists have been investigated.Hyperprolactinaemia is also a side-effect of the conventional, and some of the second-generation, antipsychotics used in the treatment of schizophrenia. These agents rely on their dopamine antagonistic properties to provide their antipsychotic effects. However, this also removes the brake on prolactin secretion, leading to hyperprolactinaemia. While antipsychotic use has been linked to certain hyperprolactinaemia-related side-effects (sexual dysfunction), its link to others (decreased bone mineral density) has proved more controversial. The association of symptoms with antipsychotic use is further complicated by the fact that patients with schizophrenia can suffer from some of these symptoms because of the disease itself.In managing antipsychotic-induced hyperprolactinaemia, the initial step is to exclude other causes of hyperprolactinaemia while monitoring the occurrence of adverse effects. The physician should also engage in close consultation with the patient with regard to the benefits of the antipsychotic medication and the impact of any adverse effects. A regular risk-benefit discussion will allow the clinician to achieve optimal outcomes in each case.

Antipsychotics

The different groups of classical antipsychotic drugs (pheno-thiazines, thioxanthenes, butyrophenones) have slightly different pharmacological profiles, but all have dopamine antagonist properties and most have some α-adrenergic antagonist activity. Many phenothiazines also have anticholinergic and antihistamine activity. The risk of arryhthmia is most likely a result of potassium channel blockade, and it seems to be more common with certain drugs in this class (e.g. thioridazine). 'Atypical' antipsychotics (e.g. clozapine, olanzapine, risperidone) are also dopamine antagonists.

Behavioural pharmacology of polygalasaponins indicates potential antipsychotic efficacy

Polygalasaponins were extracted from a plant ( Polygala tenuifolia Willdenow) that has been prescribed for hundreds of years to treat psychotic illnesses in Korean traditional medicine. Previous in vitro binding studies suggested a potential mechanism for its antipsychotic action, as polygalasaponin was shown to have an affinity for both dopamine and serotonin receptors [Psychopharmacol. Bull. 31 (1995) 139.]. In the present study we have investigated the functional in vivo actions of this material in tests that are predictive of dopamine and serotonin antagonist activities. Polygalasaponin (25–500 mg/kg) was shown to produce a dose-related reduction in the apomorphine-induced climbing behaviour (minimum effective dose [ED min] 25 mg/kg ip, 250 mg/kg sc and po), the 5-hydroxytryptamine (5-HTP)-induced serotonin syndrome (ED min 50 mg/kg ip) and the MK-801-induced hyperactivity (ED min 25 mg/kg ip) in mice. This compound also reduced the cocaine-induced hyperactivity (ED min 25 mg/kg ip) in rats. These results demonstrated that polygalasaponin has dopamine and serotonin receptor antagonist properties in vivo. This might suggest its possible utility as an antipsychotic agent.

The novel atypical antipsychotic olanzapine, but not the CCK-B antagonist LY288513, blocks apomorphine-induced disruption of pre-pulse inhibition

Pre-pulse inhibition (PPI) of the acoustic startle response is the diminution of the startle response when the startle stimulus is preceded by a weaker, non-startle-eliciting stimulus. Deficits in PPI occur in animals following the administration of apomorphine and in schizophrenic patients. In this study, we examined the ability of the novel atypical antipsychotic olanzapine and the cholecystokinin (CCK)-B antagonist LY288513 to reverse the apomorphine-induced disruption of pre-pulse inhibition. Olanzapine (3.0 and 5.0 mg/kg, i.p.), but not LY288513 (1.0–100 mg/kg, p.o.), blocked apomorphine-induced disruption of PPI. These results indicate that olanzapine, but not LY288513, has dopamine antagonist properties in vivo and predict that olanzapine, but not LY288513, will have antipsychotic activity in man.

Comparative dopaminergic and muscarinic antagonist activity of clozapine and haloperidol

Clozapine is an atypical antipsychotic drug, and its dopamine and muscarinic antagonist activity has been compared with haloperidol in rodents. Elevation in rat striatal acetylcholine (ACh) and mice cerebellar cGMP has been used as an agonist response for oxotremorine and quinpirole. Pretreatment with clozapine significantly blocked oxotremorine-induced elevation in striatal ACh ( p < 0.01) and cerebellar cGMP ( p < 0.05). At the same doses, clozapine had no significant effect on quinpirole-induced increases in ACh and cGMP levels. Pretreatment with haloperidol significantly antagonized quinpirole-induced elevation in striatal ACh ( p < 0.01) and cerebellar cGMP ( p < 0.05), and haloperidol had no significant effect on oxotremorine-induced agonist responses. Thus, clozapine is antimuscarinic at a dose level that lacks dopamine antagonist properties, whereas haloperidol is a dopamine antagonist and lacks antimuscarinic activity. The atypical neuroleptic profile of clozapine may be due to its high antimuscarinic and low antidopaminergic activity.

The atypical neuroleptic clozapine (Leponex)--current knowledge and recent clinical aspects

The dibenzoepine derivative clozapine is seen as a prototype of an atypical neuroleptic, because clozapine has good antipsychotic efficacy but only minimal dopamine antagonistic properties in common animal paradigms. The latter is reflected by the observation that extrapyramidal symptoms during clozapine are a rare phenomenon. Furthermore, recent studies in the USA demonstrated a superior efficacy of clozapine in schizophrenic patients who are nonresponsive to classic neuroleptics. Therefore, the introduction of clozapine in the USA was performed in 1990 despite the well-known risk of agranulocytosis (1-2% during the first year of treatment); however, under restricted conditions regarding the mandatory weekly control of the white blood cell count. For the use of clozapine in Europe, it should be underlined that in 1992 the indication was restricted to "acute and chronic forms of schizophrenia" whereas formerly it was permitted to treat several other neuroleptic resistant syndromes with clozapine, e.g. severe psychotic excitement, aggressive behavior or manic or atypical psychosis. The usage of clozapine in these indications is now only permitted under the restricted legal conditions of a "therapeutic trial" in selected patients. However, several indications for which clozapine has been used successfully in Europe are currently re-investigated in the USA, hopefully leading to a redefinition and extension of the indication spectrum. On the other hand, the American multicenter trials lead to the conclusion that the treatment with clozapine is not furthermore the treatment of last choice but a serious therapeutic alternative which should be available for all schizophrenic patient in case of neuroleptic resistance or of severe side effects of standard neuroleptics. Clozapine treatment leads to an improvement of the quality of life in one third of these schizophrenics and, moreover, results in a marked reduction of costs mainly by reducing the rehospitalisation rates. On the other hand, the list of well-known side effects of clozapine (e.g. agranulocytosis, increased risk of seizures, initial sedation) has to be extended (e.g. transient leucocytosis or eosinophilia, rare but severe complications like cardiorespiratory arrest and "sudden death" during combination with benzodiazepines, case reports of pericarditis, pancreatitis or polyserositis). On the background of possible cardiorespiratory complications we recommend to start the first treatment with clozapine in high risk patients (e.g. those in older age or in case of organic brain impairment) only in restricted indications and only in centers with sufficient clozapine experience.

METOCLOPRAMIDE‐INDUCED EXTRA PYRAMIDAL SYMPTOMS IN A DIABETIC PATIENT

To the Editor: Metoclopramide is a commonly prescribed peristaltic, antiemetic, and antinauseant.1,2. It has dopamine antagonist properties, both centrally and peripherally, and may increase sensitivity to peripheral cholinergic transmission.1–3. The major adverse neuropsychiatric effects seen with this medication are acute dystonias, akathisia, parkinsonian symptoms, tardive dyskinesia (TD), and neuroleptic malignant syndrome.1,3–5. These symptoms may go misdiagnosed as a comor-bid neurologic or psychiatric condition,3,4 which could lead to the administration of psychotrophic medications thereby compounding the problem. The following case illustrates the potential risks of dopamine antagonism in the elderly. Mr. D. is a 76-year-old male, with essential hypertension, non-insulin-dependent diabetes mellitus, and gastroesopha-geal reflux, who presented with restlessness, purposeless activity, scuffling gait, mild cogwheel rigidity, and bradykinesia. These symptoms started suddenly after he began taking metoclopramide 10 mg BID. The movements, which were exacerbated by anxiety and stress, did not respond to antiparkin-sonian agents or benzodiazepines. Serial head CAT scans were unremarkable. As a result, Mr. D. had become dependent on a wheelchair for the thirty days prior to his admission. His medications include chlorpropamide 100 mg BID, metoclopramide 10 mg BID, lorazepam 0.5-1.0 mg PRN q HS, gemfibrozil 600 mg BID, and metoprolol tartrate 100 mg/ hydrochlorothiazide 25 mg 1 qd. Thirty-six hours after the metoclopramide was discontinued, Mr. D. was able to ambulate unsteadily without assistance and continued to improved gradually thereafter. Upon discharge 10 days later, he no longer exhibited rigidity or bradykinesia. Subjectively he reported inner calm, and objectively he appeared less restless. The relative risk for metoclopramide-induced persistent and asymmetric movement disorders has been found to increase with age, female gender, and some intercurrent illnesses1,6. Mr. D. possessed two of these three risk factors, which placed him at high risk for occurrence and increased severity of adverse neuropsychiatric symptoms. For reasons not understood, diabetes mellitus confers an added risk factor for extrapyramidal symptoms.7–9. Incidence studies have shown a 2: 1 risk ratio for TD in diabetics when compared with nondiabetics7–9. Metoclopramide-treated diabetics have also shown a significantly greater severity of TD than metoclopramide-treated nondiabetics.1,7 The comorbid state of diabetes and gastroesophageal reflux may predispose this patient population to the added risks of extrapyramidal side effects caused by dopamine antagonistic medications. It is important to recognize and differentiate iatrogenic drug-induced reactions from enduring medical conditions. The medication-sensitive geriatric population lends itself well to this common predicament and, therefore, requires clinical prudence. Additionally, this population often brings with it concurrent illnesses that further complicate their treatment. This is well illustrated by the case of Mr. D., whose age and comorbid medical condition placed him at increased risk for more severe extrapyramidal side effects seen with antidopaminenergic agents. Physicians need to be aware of these synergistic risk factors and take the appropriate steps in order to avoid exacerbation of the primary condition. First line course of action with the geriatric population may be treatment with less potent, and with peripherally acting medications, when available.

Dopamine receptor antagonist properties of S 14506, 8-OH-DPAT, raclopride and clozapine in rodents

S 14506 (1-[-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphthyl)piperazine hydrochloride), 8-OH-DPAT ((±)-8-hydroxydipropylaminotetralin hydrobromide), clozapine and raclopride were compared in some behavioural models able to characterize dopamine antagonist properties. In mice treated with apomorphine (0.75 mg/kg, s.c.), stereotyped climbing and sniffing were dose dependently antagonized by S 14506, by clozapine and by raclopride, but were virtually not modified by 8-OH-DPAT. Stereotyped climbing and sniffing induced by (+)-amphetamine (1.25 mg/kg, s.c.) in mice treated with L-DOPA ( L-3,4-dihydroxyphenylalanine 75 mg/kg, associated with benserazide, i.p.) were also dose dependently antagonized by S 14506 and by raclopride, but were only partially antagonized by clozapine and unaffected by 8-OH-DPAT. Grooming behaviour induced by SK&F 38393 ((±)-1-phenyl-2,3,4,5-tetrahydro-(1 H)-3-benzazepine-7,8-diol hydrochloride, 1.87 mg/kg,s.c.) in mice was inhibited by low doses of S 14506 and of clozapine, and by relatively high doses of 8-OH-DPAT and of raclopride. The decreased grooming behaviour observed in apomorphine-treated mice was partly antagonized by high doses of raclopride but was significantly potentiated by S 14506, 8-OH-DPAT and clozapine. Raclopride produced the same effect in mice treated with (+)-amphetamine and L-DOPA. In rats treated with apomorphine (0.6 mg/kg, s.c.), sniffing was dose dependently antagonized by S 14506, by raclopride and by clozapine, but not by 8-OH-DPAT. Again, whereas increasing doses of raclopride allowed grooming to reappear in apomorphine (0.6 mg/kg)-treated rats, S 14506, 8-OH-DPAT and clozapine did not. Raclopride induced catalepsy in rats, whereas like clozapine, S 14506 was virtually ineffective. All the tested compounds inhibited in vitro [ 3H]raclopride binding in rat striatum (raclopride > S 14506 > clozapine > 8-OH-DPAT), whereas only clozapine inhibited [ 3H]SCH 23390 binding. Finally, S 14506 inhibited the in vivo binding of [ 3H]raclopride in striatum and olfactory bulbs, but did not affect the striatal in vivo binding of [ 3H]SCH 23390. From these data, it appears that like raclopride, S 14506 displays dopamine antagonist properties by blocking dopamine D 2 receptors. However, the psychopharmacological profile of S 14506 is closer to that of clozapine than to that of raclopride, probably as a result of its actions at 5-HT receptors.

Centrally acting serotonergic and dopaminergic agents. 1. Synthesis and structure-activity relationships of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives.

The synthesis and structure-activity relationships (SAR) of 2,3,3a,4,5,9b-hexahydro-1H-benz[e]indole derivatives (3) are described. These compounds are conformationally restricted, angular tricyclic analogs of 2-aminotetralin. The synthesis was achieved in several steps from the corresponding 2-tetralones. The enantiomers of the cis analogs were obtained from either fractional recrystallizations of the diastereomeric salts of di-p-toluoyl-L-(or D)-tartaric acid or an asymmetric synthesis using chiral (R)-alpha-methylbenzylamine. All analogs were evaluated in the in vitro 5-HT1A and D2 binding assays and selected analogs were investigated further in biochemical and behavioral tests. Analogs with 9-methoxy substitution (R1 in 3) showed mixed 5-HT1A agonist and dopamine antagonist activities whereas the corresponding 9-hydroxy analogs displayed selective 5-HT1A agonist activity. The cis analogs were found to be more potent than the corresponding trans analogs and in the cis series, the (3aR)-(-)-enantiomers displayed higher potency. Nitrogen substitution (R2 in 3) with either an n-propyl or an allyl group produced similar activities whereas replacement with a bulky alpha-methylbenzyl group resulted in loss of activity. Analogs without aromatic substitution (R1 = H in 3) still showed good 5-HT1A agonist activity, although less potent than the 9-methoxy series. In this case, the trans analogs possessed equal or higher in vitro 5-HT1A affinity than the corresponding cis analogs. Analogs with either 6-methoxy or 6-hydroxy substitution (R1 in 3) were found to display dopamine antagonist properties. However, only N-allyl analogs showed this activity. In the 6-methoxy-N-allyl series, the cis analog was found to be more potent than the trans analog. Again, between the pair of cis enantiomers, the (3aR)-(-)-enantiomer showed higher potency. Incorporation of an additional methyl group into 9-methoxy cis analogs at C-2 resulted in retention of potent 5-HT1A agonist activity.

HOW COMMONLY DOES METOCLOPRAMIDE CAUSE MOVEMENT DISORDERS

Metoclopramide is often used to treat diabetic gastroparesis, esophageal reflux, and nausea from chemotherapy. The drug's dopamine antagonist properties may cause extrapyramidal side effects, but these complications are thought to be rare. This study compared 51 patients (mean age, 64) …

Adverse Neuropsychiatric Effects of Dopamine Antagonist Medications: Misdiagnosis in the Medical Setting

Medications with central dopamine antagonist properties are in wide use in treating a variety of medical symptoms. Some of the most commonly used are metoclopramide (Reglan), prochlorperazine (Compazine), droperidol (Inapsine), and promethazine (Phenergan). The major adverse neuropsychiatric effects seen with these medications are acute dystonias, akathisia, parkinsonian symptoms, and neuroleptic malignant syndrome. These effects are often unrecognized or misdiagnosed by the primary physician as functional psychiatric disorders. The authors present four cases in which adverse neuropsychiatric effects from metoclopramide and prochlorperazine occurred with patients in the general hospital, and they discuss their initial misdiagnosis and subsequent identification and treatment by the consulting psychiatrist. The literature is reviewed on the adverse neuropsychiatric effects of metoclopramide and prochlorperazine, with attention to patient populations at risk. The authors believe that there is a key role in this area for the consulting psychiatrist, who can provide diagnostic clarity, advice on management, and ongoing staff education.