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Successful augmentation of clozapine-resistant treatment of schizophrenia with clonidine

Progress in Neuro-Psychopharmacology & Biological Psychiatry xxx (2010) xxx–xxx Progress in Neuro-Psychopharmacology & Biological j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p n p Successful augmentation of clozapine-resistant treatment of noticed that he was more communicative and that he spontaneously initiated actions like answering the phone or watching television,unlike before. Given the limited improvement, clonidine was stoppedafter 4 months and clozapine was offered as a substitute (up to400 mg/d, titration above 400 mg/d was precluded by significant enduring sedation). Clozapine was well tolerated at this dosage andthe patient had no hypersialhorrhea. He gradually improved and Clozapine is considered the reference for antipsychotic agent participated in day hospital activities, but his hallucinations were still because of its superior clinical efficacy in treatment-resistant very impairing after two years of treatment. In November 2006, schizophrenia. Nevertheless, 40% to 70% of neuroleptic-resistant Transcranial Magnetic Stimulation (TMS) of the temporal region was schizophrenic patients are nonresponders to clozapine preferred to electroconvulsivotherapy in the absence of suicidality and dangerous behavior, and Mr. K. received 10 sessions without strategies have come into clinical practice although often without success. Aripiprazole (15 mg/d) was added to clozapine. He became more talkative, his deficit symptomatology improved but he was still It has been proposed that a relatively potent blockade of 5-HT(2A) suffering from intense hallucinations. Two years later, in February receptors coupled with the weaker antagonism of the dopamine D(2) 2008, a second trial of TMS was successful and the patient considered receptors may play a critical role in the mechanism of action of himself to be half-improved. Four months later, his hallucinations atypical antipsychotic drugs such as clozapine ( became unbearable again. The patient only accepted clonidine ). also suggested that the antagonism of α2- (0.75 mg/d) to be added to clozapine–aripirazole combination. A adrenergic receptors by clozapine may contribute to its superior dramatic improvement was observed within three days. He felt that effects. Meanwhile, successfully used clonidine, an his hallucinations “vanished” and his distress disappeared. The AHRS α2-adrenergic receptor agonist which decreases noradrenergic score was still 26: he explained that his “voices” were much less neuron firing and release through presynaptic action painful and distressing. After 9 months of adjuvant treatment, the ), to treat a subset of patients with residual schizophrenia who AHRS score progressively fell between 13, and 17 (−35 to −50%). All relapsed after withdrawal of their usual treatment; aspects of hallucinatory experience were improved. Tolerability was also used clonidine to treat the hallucinatory «flashbacks» excellent; blood pressure always remained within normal limits.
Delusions persisted but without emotional participation. Mr. K had a Thus, we successfully added clonidine in a case of resistance to much better emotional rapport with others, began to read books, joined a football team, and enjoyed answering to TV games such as“questions for a champion” he watched with his parents.
Mr. K was a 28-year-old unemployed male with 11 years of education, non-smoker and drinking tea. He was hospitalized for afirst episode of schizophrenia lasting for 2 years in December 2002 This patient presented a treatment-resistant schizophrenia that and was treated 8 weeks with olanzapine (20 mg/d) before receiving failed to respond to three antipsychotics, including clozapine, each haloperidol (30 mg/d followed by haloperidol decanoate (250 mg/ prescribed at appropriate dosages during at least 8 weeks. It also month)). Six months after discharge, he was seen for a second advice failed to respond to a clozapine–aripirazole combination prescribed as he still suffered from severe auditory hallucinations accompanied during more than 14 months. TMS resulted in a robust improvement by delusions of thought broadcasting and convictions to have a special of short duration. This may argue against both a placebo-effect and a mission. Most of the day, he was staying in his room, only meeting his time-effect of the addition of clonidine. No therapeutic-drug- parents for lunch and dinner. Contact was poor with a flat speech, monitoring was performed but the good tolerance of the clonidine- little visual contact, delayed and laconic answers; auditory hallucina- antipsychotics combination suggests that pharmacokinetic interac- tions were perceived as coming from both external and internal tions resulting in higher clozapine serum levels may not explain the sources, making a running and aggressive commentary of the apparent efficacy of this combination.
patient's thoughts or actions, producing much anxiety. His score on Clonidine has been used in many mental disorders and warrants the Hofmann's Auditory Hallucinations Rating Scale—assessing the blood pressure monitoring and gradual discontinuation in order to frequency, reality, loudness, number and length of voices, attentional salience and associated level of distress—was 32/41 (AHRS, Ten small-size trials of clonidine in schizophrenia have been ). As hallucinations were the most prominent and inconclusive. Clonidine is not uncommonly prescribed in similar impairing symptoms, clonidine was added to his regimen dosages to patients on clozapine to alleviate iatrogenic hypersaliva- (0.075 mg/d up to 0.225/d). Within six weeks, his score progressively tion ) but the eventual therapeutic effect of fell to 25 (−22%). Mr K. asked to pursue this treatment. His parents clonidine may have been confounded with the efficacy of clozapine.
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doi: Please cite this article as: Dardennes RM, et al, Successful augmentation of clozapine-resistant treatment of schizophrenia with clonidine,Prog Neuro-Psychopharmacol Biol Psychiatry (2010), doi: This was not the case for our patient who was still impaired under a Lechin F, van der Dijs B, Gomez F, Valls JM, Acosta E, Arocha L. Pharmacomanometric studies of colonic motility as a guide to the chemotherapy of schizophrenia. J Clin stable and prolonged dosage of clozapine before the addition of Lerner AG, Finkel B, Oyffe I, Merenzon I, Sigal M. Clonidine treatment for hallucinogen The mechanism of action of clonidine remains hypothetical.
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in clozapine-resistant schizophrenia. The striking improvement Tollefson GD, Birkett MA, Kiesler GM, Wood AJ, Lilly Resistant Schizophrenia Study Group. Double-blind comparison of olanzapine versus clozapine in schizophrenic observed in this case in the absence of any adverse effects suggests patients clinically eligible for treatment with clozapine. Biol Psychiatry 2001;49: that controlled trials of clonidine augmentation in clozapine-resistant schizophrenia may be of clinical importance.
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Faculty of Medicine Paris Descartes, 15 rue de l'Ecole de Médecine, Hospital Sainte-Anne, 1 rue Cabanis, Cedex 14, F-75674 Paris, France Center of Psychiatry and Neurosciences, INSERM U894, Prof. Dardennes treated the patient and collected the data. Miss Al 2ter rue d'Alésia, F-75014 Paris, France Anbar and Prof. Dardennes managed the literature searches and Graduate School Brain-Cognition-Behavior (ED3C No. 158), analyses, and wrote the first draft of the manuscript. Prof. Rouillon 9 Quai Saint Bernard, Bat B, 7th floor, door 700, contributed to the revision of the first draft. All authors contributed to and have approved the final manuscript.
⁎ Corresponding author. Clinique des Maladies Mentales et de l'encéphale, 100, rue de la Santé 75674 Paris Cedex 14, France.
Tel.: +33 1 45 65 86 39; fax: +33 1 45 65 89 43.
Prof. Dardennes and Rouillon have consulted for pharma compa- nies (Lilly, Otsuka, Lundbeck, Janssen, Sanofi). All other authors declare that they have no conflict of interest.
Graduate School Brain-Cognition-Behavior (ED3C No. 158), 9 Quai Saint Bernard, Bat B, 7th floor, door 700, We thank Miss Stéphanie Prouteau, who assisted in the prepara- tion and proof-reading of the manuscript.
Faculty of Medicine Paris Descartes, 15 rue de l'Ecole de Médecine, Hospital Sainte-Anne, 1 rue Cabanis, Cedex 14, F-75674 Paris, France Center of Psychiatry and Neurosciences, INSERM U894, Arnsten AFT. Adrenergic targets for the treatment of cognitive deficits in schizophrenia.
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Please cite this article as: Dardennes RM, et al, Successful augmentation of clozapine-resistant treatment of schizophrenia with clonidine,Prog Neuro-Psychopharmacol Biol Psychiatry (2010),


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