Partial Dopamine Agonist Research Articles

Four Cases of Chronic Pain That Improved Dramatically Following Low-Dose Aripiprazole Administration

To the Editor: The role played by the brain's dopamine system in pain control has garnered attention in recent years.1 Herein, we report 4 cases of long-term chronic pain (pain disorder [DSM-IV-TR]) that improved dramatically following administration of a low dose of aripiprazole, a partial dopamine agonist. None of these 4 patients satisfied the DSM-IV-TR diagnostic criteria for schizophrenia. Case 1. Mr A, a 42-year-old man, had a chief complaint of chronic head and neck pain that had persisted for 10 years and was refractory to administration of morphine 70 mg/d. He visited our department in December 2008 and was diagnosed with pain disorder and pervasive developmental disorder. Although fluvoxamine treatment was started, with the dosage gradually increased to 200 mg/d, it was ineffective and the pain exacerbated. Upon switching to aripiprazole 3 mg/d, the pain improved dramatically, and the patient was able to discontinue morphine. After increasing the dose to 6 mg/d, the patient became able to go fishing for the first time in a few years, and his motivation increased. Case 2. Mr B, a 35-year-old man, had chronic back and leg pain that had persisted for 15 years and particularly worsened following sexual intercourse. He had visited over 20 medical institutions in the past and had not responded to antidepressants. He visited our department in March 2009 and was diagnosed with pain disorder. Pain disappeared after initiation of aripiprazole 2 mg/d, and the patient's passion for his work in computer software development improved. As aripiprazole was effective in the treatment of pain disorder in Cases 1 and 2, we subsequently also used it for Cases 3 and 4, and it was effective. Below are concise descriptions of Cases 3 and 4. Case 3. Ms C, an 83-year-old woman, had developed Parkinson's disease and back and leg pain (pain disorder) 4 years before. She visited our department in August 2009. Pain improved following administration of aripiprazole 3 mg/d, and the patient began going out rather than staying home as she had been, and her level of activity improved. Case 4. Ms D, a 68-year-old woman, had developed pain at the top of the head (pain disorder) a year before she visited our department in October 2009. Pain disappeared after we added aripiprazole 2 mg/d to sertraline 100 mg/d, and the patient's motivation toward housework improved. These 4 patients were characterized by reduction of pain and improved motivation following low-dose aripiprazole administration. Dopamine plays a role in pain processing via μ opioids.1 Dopamine-related diseases often exhibit pain-related symptoms. For example, pain is a common complaint among patients with Parkinson's disease,2 and those with schizophrenia are known to have a reduced pain sensitivity.3 In other words, the degree of dopamine system activation is inversely proportional to the degree of pain. These 4 cases suggest that aripiprazole, a dopamine system stabilizer, may be a therapeutic option for chronic pain.

Brain extracellular levels of the putative antipsychotic CI-1007 and its effects on striatal and nucleus accumbens dopamine overflow in the awake rat.

The compound CI-1007 (R-(+)-1,2,3,6-tetrahydro-4-phenyl-1 [(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine maleate) has been identified as a partial dopamine agonist and putative antipsychotic in in-vitro and in-vivo neurochemical, neurophysiological and behavioural tests. By use of microdialysis in conjunction with high-performance liquid chromatography (HPLC) with electrochemical detection, the effects of the drug on brain dopamine release, previously observed in anaesthetized animals, were shown to occur in awake animals also. Detection of peripherally administered CI-1007 in the brain, i.e. evidence of the drug's ability to penetrate the blood-brain barrier, was achieved by use of in-vivo brain microdialysis in awake, freely moving rats and capillary HPLC in combination with tandem mass spectrometry (HPLC/MS/MS). Intravenous administration of CI-1007 (40 mg kg-1) significantly inhibits dopamine release in the nucleus accumbens, a region associated with dopamine hyperactivity in schizophrenia, while having a non-significant impact on the striatal dopamine neurotransmission which is critical to regular motor function. The differential neurochemical profile of the drug indicates its potential usefulness in treating positive disease symptoms and implies that its extrapyramidal side effects are lower than those of typical antipsychotics.

Antipsychotics

Antipsychotics

An Open Randomized Pilot Trial on the Differential Effects of Aripiprazole versus Risperidone on Anhedonia and Subjective Well-Being

Negative symptoms of schizophrenia often predict an unfavorable clinical outcome. Disturbed dopamine transmission in different brain parts may underlie different aspects of negative symptoms, and the effect of antipsychotics on them may also differ. This pilot study investigated the potentially therapeutic effects of the partial dopamine agonist aripiprazole on different negative symptoms. This pilot study randomly assigned patients with schizophrenia (N=40) to either aripiprazole or risperidone. After 6 weeks of treatment, the severity of negative symptoms was determined by the PANSS. Subscales of self-report questionnaires were used to assess differences in initiative, anhedonia, social functioning and subjective well-being. Patients treated with aripiprazole showed a significant improvement on measures for anhedonia and subjective wellbeing. Negative symptoms in general, lack of initiative and social inhibition were also lower in the aripiprazole treated group, but without reaching statistical significance. According to this pilot study, aripiprazole appears to specifically improve anhedonia and subjective wellbeing compared to risperidone. This may be caused by a specific effect of aripiprazole on the limbic branch of the dopamine system. Future studies should replicate this finding with a larger sample size.

The dopamine and cAMP regulated phosphoprotein, 32 kDa (DARPP-32) signaling pathway: A novel therapeutic target in traumatic brain injury

Traumatic brain injury (TBI) causes persistent neurologic deficits. Current therapies, predominantly focused upon cortical and hippocampal cellular survival, have limited benefit on cognitive outcomes. Striatal damage is associated with deficits in executive function, learning, and memory. Dopamine and cAMP regulated phosphoprotein 32 (DARPP-32) is expressed within striatal medium spiny neurons and regulates striatal function. We found that controlled cortical impact injury in rats produces a chronic decrease in DARPP-32 phosphorylation at threonine-34 and an increase in protein phosphatase-1 activity. There is no effect of injury on threonine-75 phosphorylation or on DARPP-32 protein. Amantadine, shown to be efficacious in treating post-TBI cognitive deficits, given daily for two weeks is able to restore the loss of DARPP-32 phosphorylation and reduce protein phosphatase-1 activity. Amantadine also decreases the phosphorylation of threonine-75 consistent with activity as a partial N-methyl-D-aspartate (NMDA) receptor antagonist and partial dopamine agonist. These data demonstrate that targeting the DARPP-32 signaling cascade represents a promising novel therapeutic approach in the treatment of persistent deficits following a TBI.

Open-label study comparing the efficacy and tolerability of aripiprazole and haloperidol in the treatment of pediatric tic disorders

Due to its unique pharmacodynamic properties of dopamine partial agonist activity, and its association with few and mild side effects, aripiprazole is a candidate atypical antipsychotic for patients with tic disorders. This open-label study compared the efficacy and tolerability of aripiprazole with haloperidol, a typical antipsychotic widely used to treat patients with tic disorders. Forty-eight children and adolescents with tic disorders were recruited from the outpatient clinic at South Korea and treated with aripiprazole (initial dose, 5.0 mg/d; maximum dose 20 mg/d) or haloperidol (initial dose, 0.75 mg/d; maximum dose, 4.5 mg/d) for 8 weeks. Treatment efficacy was measured using the yale global tic severity scale (YGTSS), and tolerability was measured using the extrapyramidal symptom rating scale (ESRS) and an adverse effects checklist. Total tic scores as measured by the YGTSS decreased over time in both groups (p < 0.001) without any significant differences between groups. ESRS scores were significantly higher in the haloperidol group during the 4 weeks after commencement of medication (p < 0.05). These results indicate that aripiprazole may be a promising drug in the treatment of children and adolescents with tic disorders. Further controlled studies are needed to determine the efficacy and tolerability of aripiprazole in these patients.

New-Onset Psychosis and Emergence of Suicidal Ideation With Aripiprazole

Back to table of contents Previous article Next article Communications and UpdatesFull AccessNew-Onset Psychosis and Emergence of Suicidal Ideation With AripiprazoleVithyalakshmi Selvaraj, M.D., Sriram Ramaswamy, M.D., Ashish Sharma, M.D., and Daniel Wilson, M.D.Vithyalakshmi SelvarajOmaha, NebraskaSearch for more papers by this author, M.D., Sriram RamaswamyOmaha, NebraskaSearch for more papers by this author, M.D., Ashish SharmaOmaha, NebraskaSearch for more papers by this author, M.D., and Daniel WilsonOmaha, NebraskaSearch for more papers by this author, M.D.Published Online:1 Dec 2010https://doi.org/10.1176/appi.ajp.2010.10020238AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Aripiprazole is an atypical antipsychotic approved for treatment of schizophrenia and bipolar disorder as well as use as adjunctive therapy in major depressive disorder. We report the case of an emergence of psychotic symptoms in a patient following the addition of aripiprazole to duloxetine.“Ms. L” was a 49-year-old woman with chronic depression and postoperative cellulitis following a bunion excision. She was evaluated on the medical unit. She endorsed depressive symptoms, auditory hallucinations, and suicidal thoughts. The patient had previously attempted suicide twice by drug overdose. Her most recent suicide attempt was 7 months prior. Previous responses to sertraline and citalopram were poor. At the time of assessment on the medical unit, she was receiving duloxetine (40 mg twice daily), aripiprazole (1 mg/day), clonazepam (1 mg twice daily), and amoxicillin/clavulanate (850 mg twice daily).The patient was started on duloxetine 7 months before. Ten days prior to admission, her primary care physician had started her on aripiprazole (2 mg/day) for augmentation. She denied a history of psychotic symptoms and drug or alcohol abuse as well as a family history of psychosis.Three days after starting aripiprazole, Ms. L reported auditory hallucinations. She was paranoid regarding her ex-husband. She described command hallucinations from the devil, who meant to harm her, and could also hear God's voice encouraging her not to listen to the devil. She experienced concurrent onset of suicidal ideation with no plan. She was fully oriented, with no evidence of confusion. Aripiprazole was reduced to 1 mg/day, which led to amelioration of her hallucinations. However, her suicidal thoughts and paranoid beliefs persisted.The psychiatric consultant decided to discontinue aripiprazole, leading to rapid and complete resolution of the patient's psychotic symptoms and suicidal ideation. Her ongoing depression was managed with duloxetine (60 mg twice daily).Emergence of psychotic symptoms immediately following the addition of aripiprazole suggests a causative role of the drug in the onset of the present patient's psychosis. Furthermore, improvement in this patient's psychosis upon reduction of aripiprazole as well as complete resolution of psychosis following discontinuation further support an inference that the compound was a causal agent. The patient was not started on any other medication known to potentiate psychosis. Her antibiotic regimen was instituted 9 days after starting aripiprazole. She attained menopause approximately 1 year before, which doesn't completely eliminate her predisposition to psychosis secondary to dropping estrogen levels.A diagnosis of major depressive disorder with psychotic features was ruled out, based on lack of prior history, temporal relationship between drug initiation and emergence of symptoms, and, most importantly, complete remission of psychotic symptoms on antipsychotic discontinuation.The most likely explanation for this phenomenon is aripiprazole's action as a dopamine partial agonist (1, 2). Aripiprazole alleviates psychosis by interfering with dopamine transmission, but its agonist action at the D2 receptor can intensify psychosis. There are case reports that aripiprazole worsens psychosis (3–5) and increases suicidal ideation (6), but the present case is the first, to our knowledge, in which aripiprazole apparently induced psychosis. Another possibility may be the combination of a selective serotonin reuptake inhibitor and aripiprazole, which offsets aripiprazole's dopamine-serotonin system stabilizer functioning. We recommend detailed history taking and monitoring for psychotic symptoms when using aripiprazole in the management of nonpsychotic depression.Omaha, NebraskaThe authors report no financial relationships with commercial interests.This letter was accepted for publication in June 2010.

Attenuation of reinforcing and psychomotor stimulant effects of amphetamine by aripiprazole

Partial dopamine agonists are potential medications for the treatment of amphetamine addiction. They have been hypothesized to stabilize the dopamine system by acting as antagonists during high dopaminergic tone resulting from amphetamine use and as agonists during withdrawal. Aripiprazole is an atypical antipsychotic that acts as a partial D2 dopamine and a serotonin 5-HT₁(A) agonist and a serotonin 5-HT₂(A) antagonist. The aim of the present study was to examine the effects of aripiprazole on behaviors induced and maintained by d-amphetamine. To this end, intravenous d-amphetamine self-administration [fixed ratio 3 (FR3) schedule, 0.02 mg/infusion] and d-amphetamine-induced (0, 1.5 mg/kg intraperitoneally) locomotor activity, as well as spontaneous locomotor activity and sucrose pellet selfadministration (FR3 schedule) were studied in male Wistar rats after aripiprazole (0, 0.3, 1, 3 mg/kg i.p.) administration. Aripiprazole pre-treatment resulted in bidirectional effects on amphetamine self-administration. The 1 mg/kg dose increased, and the highest dose decreased the number of amphetamine infusions. In the locomotor activity experiments, aripiprazole attenuated amphetamine-induced activity dose-dependently and tended to suppress spontaneous activity. The highest aripiprazole doses decreased also sucrose pellet self-administration. The increase in amphetamine self-administration with the intermediate aripiprazole dose, as well as the decrease in amphetamine-induced locomotor activity, suggests that aripiprazole acted as a dopamine antagonist. Suppression of amphetamine and sucrose self-administration by the highest aripiprazole dose was probably caused by non-specific effects. Together, these results indicate that under conditions of dopaminergic stimulation, aripiprazole attenuates the reinforcing and psychomotor stimulant effects of d-amphetamine, but the dose range for this effect is rather limited.

Partial Agonist Therapy in Schizophrenia: Relevance to Diminished Criminal Responsibility

Pathological gambling (PG), classified in the DSM-IV among impulse control disorders, is defined as inappropriate, persistent gaming for money with serious personal, family, and social consequences. Offenses are frequently committed to obtain money for gambling. Pathological gambling, a planned and structured behavioral disorder, has often been described as a complication of dopamine agonist treatment in patients with Parkinson's disease. It has never been described in patients with schizophrenia receiving dopamine agonists. We present two patients with schizophrenia, previously treated with antipsychotic drugs without any suggestion of PG, who a short time after starting aripiprazole, a dopamine partial agonist, developed PG and criminal behavior, which totally resolved when aripiprazole was discontinued. Based on recent advances in research on PG and adverse drug reactions to dopamine agonists in Parkinson's disease, we postulate a link between aripiprazole and PG in both our patients with schizophrenia and raise the question of criminal responsibility.

Dose-Dependent Effects of Adjunctive Treatment With Aripiprazole on Hyperprolactinemia Induced by Risperidone in Female Patients With Schizophrenia

Hyperprolactinemia is a frequent consequence of treatment with risperidone. Recent studies have suggested that aripiprazole, a partial dopamine agonist, reduces the prolactin response to antipsychotics. Thus, we examined the dose effects of adjunctive treatment with aripiprazole on the plasma concentration of prolactin in patients who had elevated prolactin levels because of risperidone treatment. Aripiprazole was concomitantly administrated to 16 female patients with schizophrenia receiving 2 to 15 mg/d of risperidone. Dosages of aripiprazole were gradually increased from 3 to 12 mg/d with 2- to 4-week intervals. Sample collections for prolactin were conducted before aripiprazole administration (baseline) and 2 to 4 weeks after the dose escalation of aripiprazole and just before next dose escalation. The samples were taken just before the morning dose. The plasma concentration of prolactin during aripiprazole administration (3, 6, 9, or 12 mg/d) was significantly lower than that at baseline. The mean (±SD) percent reductions at 3, 6, 9, and 12 mg/d were 35% ± 14%, 54% ± 17%, 57% ± 19%, and 63% ± 17%, respectively. However, neither the plasma concentration of prolactin nor the reduction ratio differed among the dosages of 6, 9, and 12 mg/d of aripiprazole. Three out of 8 patients with amenorrhea improved after 12 mg/d of aripiprazole. The present study suggests that adjunctive treatment with aripiprazole reduces the prolactin concentration that had been increased because of risperidone treatment. The effect occurs even when a low dosage (3 mg/d) of aripiprazole was used and achieves a plateau at dosages beyond 6 mg/d.

The partial dopamine agonist pardoprunox (SLV308) administered in combination with l-dopa improves efficacy and decreases dyskinesia in MPTP treated common marmosets

Dopamine agonist treatment in early Parkinson's disease (PD) induces less dyskinesia than l-dopa. However, once dyskinesia has developed, dopamine agonists administered with l-dopa exacerbate involuntary movements. The dopamine partial D2/D3 agonist pardoprunox reverses motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-treated primates without hyperactivity, indicating that pardoprunox may alleviate dyskinesia without compromising l-dopa's beneficial actions. This study examines a clinical scenario in which pardoprunox was introduced, in an l-dopa sparing strategy, to existing l-dopa treatment in MPTP-treated marmosets previously primed to express dyskinesia. l-Dopa (5–10 mg/kg) produced effects, which were stable over the 13 treatment days, of increased locomotor activity, reversed motor disability and marked dyskinesia. Pardoprunox (SLV308; 0.0125–0.025 mg/kg) plus l-dopa (3–10 mg/kg) administration increased locomotor activity over the same treatment period and initially produced an equivalent reversal of motor disability compared to l-dopa, however this effect was enhanced as treatment progressed. This reflected the prolonged duration of effect of pardoprunox compared to that of l-dopa. While pardoprunox plus l-dopa treatment initially produced dyskinesia to the same extent as l-dopa alone, the intensity diminished as treatment progressed and it was significantly different at the end of the study. On subsequent l-dopa challenge there was no difference in motor disability reversal between those animals previously treated with pardoprunox plus l-dopa compared to l-dopa alone but the combination treatment produced significantly less dyskinesia. These data suggest that pardoprunox may provide therapeutic benefit in mid to late stage PD by reducing dyskinesia while maintaining efficacy when used with concomitant l-dopa treatment.

The dopamine D 2 partial agonist and antagonist terguride decreases heroin self-administration on fixed- and progressive-ratio schedules

Dopamine partial agonists have been suggested to be potential therapeutic candidates for pharmacological intervention in drug addiction. These drugs bind to dopamine receptors with high affinity and low intrinsic activity and are hypothesized to behave as functional antagonists in conditions of high dopaminergic tone. The aim of the present study was to characterize the effects of terguride, a partial dopamine agonist at the dopamine D 2 receptor, on intravenous heroin self-administration on fixed- and progressive-ratio schedules of reinforcement. The effects of terguride on oral sweet solution (4% sucrose) self-administration on a fixed-ratio schedule were also tested. Terguride dose-dependently decreased heroin self-administration on the fixed-ratio schedule and decreased the maximum number of responses for heroin self-administration on a progressive-ratio schedule. In contrast, terguride did not significantly affect oral sucrose self-administration. These data suggest that terguride may represent a novel pharmacological strategy for the treatment of opiate addiction.

Obsessive-Compulsive Disorder and Tourette's Disorder: Where Are We Now?

Obsessive-Compulsive Disorder and Tourette's Disorder: Where Are We Now?

Medications Acting on the Dopaminergic System in the Treatment of Alcoholic Patients

An extensive literature supports the role of dopamine in the development and maintenance of alcohol dependence. Yet the organization of brain dopamine is complex, with multiple dopamine receptor subtypes and distinct effects on reinforcement, craving, motivation and behavior. Several modestly effective pharmacological treatments for alcoholism, including naltrexone, baclofen and ondansetron, affect dopaminergic systems indirectly. Direct dopamine antagonists, including tiapride, quetiapine, ondansetron and clozapine have been shown to be somewhat effective in reducing alcohol consumption in controlled clinical trials. The partial dopamine agonist, aripiprazole has shown mixed efficacy. Dopaminergic medications can have significant side effects. A better understanding of how dopamine affects the various aspects of addictive behavior may lead to more effective medications.

From receptor pharmacology to improved outcomes: individualising the selection, dosing, and switching of antipsychotics

Determinants of antipsychotic selection and response include parameters of the primary disorder, psychiatric and physical comorbidities, past treatment effects, patient preferences, availability and acceptability of different treatments and formulations, as well as expected efficacy and safety. In the absence of consistent and sufficiently large efficacy differences among antipsychotics (except for clozapine in refractory patients), and in view of a greater focus on physical health, functional outcomes and quality of life, relatively more predictable differences in adverse events have become an important management consideration. Treatments are often selected because of a relatively lower propensity for extrapyramidal and sexual side effects, sedation, and, especially, the reduced development of cardiometabolic risk states and disorders. In this context, differences in receptor binding affinity, intrinsic activity and in the half life of antipsychotics are crucial to adopt adequate dosing and switching strategies. Dopamine rebound phenomena can occur when the level of dopamine blockade is not kept relatively constant during the switch process. This can happen when the new antipsychotic is underdosed or not fully absorbed, the switch is too abrupt from an antipsychotic with a short half life to one with a much longer half life, or when a dopamine antagonist is switched too fast to an antipsychotic with markedly less dopamine affinity or to a partial dopamine agonist. Intra-switch destabilization can also occur when changing too quickly from antipsychotics with strong histaminergic and/or cholinergic blockade to ones with lower affinity to these receptors. Overlapping “plateau” switch strategies and transient co-treatment with calming medications, such as benzodiazepines, have emerged as potential solutions to these rebound phenomena that can complicate the early switch period. To optimize outcomes, antipsychotic treatment should be pharmacologically informed and measurement based, combining both acute and long-term management goals and balancing efficacy and adverse effect considerations.

Pharmacological approaches to methamphetamine dependence: a focused review.

Methamphetamine dependence is a serious worldwide public health problem with major medical, psychiatric, socioeconomic and legal consequences. Various neuronal mechanisms implicated in methamphetamine dependence have suggested several pharmacological approaches. A literature search from a range of electronic databases (PubMed, EMBASE, PsycInfo, the NIDA research monograph index and the reference list of clinicaltrials.gov) was conducted for the period from January 1985 to October 2009. There were no restrictions on the identification or inclusion of studies in terms of publication status, language and design type. A variety of medications have failed to show efficacy in clinical trials, including a dopamine partial agonist (aripiprazole), GABAergic agents (gabapentin) and serotonergic agents (SSRI, ondansetron, mirtazapine). Three double-blind placebo-controlled trials using modafinil, bupropion and naltrexone have shown positive results in reducing amphetamine or methamphetamine use. Two studies employing agonist replacement medications, one with d-amphetamine and the other with methylphenidate, have also shown promise. Despite the lack of success in most studies to date, increasing efforts are being made to develop medications for the treatment of methamphetamine dependence and several promising agents are targets of further research.

Double‐blind study of pardoprunox, a new partial dopamine agonist, in early Parkinson's disease

This study examined the efficacy and safety of the partial dopamine agonist, pardoprunox (SLV308), in the treatment of patients with early Parkinson's disease (PD). Patients were randomized to receive pardoprunox (n = 69) or placebo (n = 70). Pardoprunox was titrated to each patient's optimal dose (9-45 mg/d) over 2 to 6 weeks and then maintained at this dose for a further 3 weeks. Concomitant anti-Parkinson treatment was not permitted. In the primary analysis, Unified PD Rating Scale (UPDRS)-Motor score was improved in pardoprunox-treated patients (overall mean dose 23.8 mg/d; -7.3 points), as compared with placebo (-3.0 points; P = 0.0001), from baseline to end point. At end point, there were more responders (> or = 30% reduction in UPDRS-Motor score) in the pardoprunox group (50.7%) than in the placebo group (15.7%; P < 0.0001). In other secondary analyses, UPDRS-activities of daily living (ADL) and -ADL+Motor scores were also significantly more improved in the pardoprunox group. Nausea was reported by 32 of 68 (47.1%) pardoprunox-treated patients (vs. 3/70, 4.3%, placebo-treated patients), with dizziness, somnolence, headache, and asthenia also reported by > or = 10 patients. In this exploratory proof-of-concept study, pardoprunox significantly improved motor function in patients with early PD. The efficacy and safety profile of pardoprunox justifies its further investigation in PD.

Aripiprazole for olanzapine-induced symptomatic hyper prolactinemia

Sir, Aripiprazole is a novel atypical antipsychotic medication as it is a potent dopamine partial agonist and also acts as a partial agonist at serotonin (5-HT)1A and as an antagonist at 5-HT2A receptors.[1] It has been theorized that dopamine partial agonists may be able to stabilize the dopaminergic system without inducing a hypo dopaminergic state, thereby reducing the risk of side effects associated with pure blockade of dopamine receptors, especially extra pyramidal and endocrinological side effects. We hereby report a patient in whom addition of aripiprazole to ongoing treatment with olanzapine resulted in resolution of olanzapine induced hyper prolactinemia. The patient: A 29-year-old married female suffering from schizophrenia since three years. Her illness was characterized by suspiciousness, muttering to self, violent, aggressive behavior and disturbed biological functions. There was no significant past or family history of any psychiatric or neurological illness. She was initially treated with risperidone and haloperidol, each in adequate dose and for adequate duration, without much response. Her family members did not agree to clozapine fearing that they would not be able to monitor the blood counts. Subsequently, she was started on olanzapine up to 20 mg per day and gradually started showing improvement in symptoms. She was maintaining well when she decreased the dose on her own and subsequently had exacerbation of her symptoms. As a result, olanzapine was increased to 25 mg per day. After about one month of this therapy, the patient started reporting breast tenderness with milky discharge from nipples. She also reported scanty menstruation. At this time, her serum prolactin level elevated and was at 47 ng / mL (normal: 1.5–19.0 ng / mL). Ancillary tests, including thyroid profile and brain computed tomography scan, were normal. In view of past non response to antipsychotic drugs, olanzapine was continued in the same dose and aripiprazole was added to olanzapine in the dose of 15 mg per day. After two weeks of this addition, her serum prolactin level was 27 ng / mL. After about a month of this, the patient's symptoms improved completely and her prolactin level was within the normal range (11 ng / ml). The patient has been maintaining well on this combination for the last six months. There are similar reports, of combining aripiprazole with risperidone and with haloperidol to offset hyper prolactinemia.[2,3] Paradoxically, there are also reports of aripiprazole causing galactorrhea.[4,5] and not being effective in treatment of hyper prolactinemia associated with antipsychotic medication.[6] Although a switch to aripiprazole is an understandable and probably useful strategy, it might not be clinically useful to switch to another antipsychotic when a patient has responded to the medication. Our case did not respond to a previous trial of risperidone and haloperidol and it was not clinically feasible to stop or taper olanzapine. Perhaps these apparent inconsistencies may be reconciled by considering that aripiprazole is a partial agonist, thereby it may act as either an agonist or an antagonist depending upon the conditions. The partial agonist property of this compound means that in the presence of dopamine hypo activity, as induced by olanzapine, aripiprazole functions as a dopamine agonist with roughly 30% intrinsic activity at postsynaptic receptors,[1] restoring tonic inhibition to anterior pituitary lactotrophs. Spontaneous prolactin decline in this case would be unlikely because the time since olanzapine exposure was short. Our report suggests that aripiprazole might be useful as an add-on therapy in patients who develop hyper prolactinemia as a side effect to another antipsychotic without affecting the clinical outcome.

P03-385 - Aripiprazole in the treatment of risperidone associated tardive dyskinesia

ObjectivesTardive dyskinesia(TD) is a syndrome characterized by repetitive involuntary movements, usually involving mouth, face and tongue and sometimes the extremities. Atypical antipsychotics are of significantly lower risk for causing tardive dyskinesia, about one-fifth comparing with first generation antipsychotics. Furthermore, there is growing evidence that they may have a therapeutic effect on TD. We present a case that demonstrated a marked improvement in risperidone-induced TD following treatment with aripiprazole.MethodMr. A is a 21-year-old single male with a DSM-IV-TR diagnosis of schizophrenia, of approximately 2 years duration. He was mainly maintained on risperidone 4-6 mg/day during this time. Upon his admittance to our clinic, he was suffering auditory hallucinations, persecutory delusions, social withdrawal and he was noticed to have had some involuntary mouth movements. The patient scored three out of four (moderate) on the ‘lips and peri-oral area’ subcategory of the- Abnormal Involuntary Movement Scale (AIMS). A cranial CT scan was unremarkable and there was no past history or family history of neuro-psychiatric disorders. He was started on aripiprazole 15 miligrams per day.ResultsWithin two weeks a marked improvement was seen in his psychotic symptoms and he scored 2 on the AIMS. Two months after starting aripiprazole, he was free of psychotic symptoms and dyskinetic movements.ConclusionAltough atypical antipsychotics are known to be associated with lower risk of developing tardive dyskinesia, psychiatrists should be aware of these rare conditions. Aripiprazole, as a partial dopamine agonist, might be an alternate pharmacotherapy in threating psychosis and atypical antipsychotic-induced TD.

Use of Aripiprazole in Clozapine Induced Enuresis: Report of Two Cases

This report describes the efficacy of combined use of aripiprazole in the treatment of a patient with clozapine induced enuresis. Aripiprazole acts as a potential dopamine partial agonist and the dopamine blockade in the basal ganglia might be one of the causes of urinary incontinence and enuresis. We speculate that aripiprazole functioned as a D2 agonist in hypodopaminergic state of basal ganglia caused by clozapine and maintained dopamine level that would improve enuresis ultimately.