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Acute Antimanic Efficacy and Safety of Intravenous Valproate Loading Therapy: An Open-Label Study

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Acute Antimanic Efficacy and Safety of Intravenous Valproate Loading Therapy: An Open-Label Study
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  Pharmacopsychiatry Editor: B. Saletu (Vienna) Original Paper Neuropsychobiology 2003;47:90–93DOI: 10.1159/000070015 Acute Antimanic Efficacy and Safety ofIntravenous Valproate Loading Therapy:An Open-Label Study K.JagadheesanHarpreetS.DuggalSubashChandraGuptaSomuyaBasuSanjeevRanjanRajivSandilSayeedAkhtarS.HaqueNizamie Central Institute of Psychiatry, Ranchi, India S. Haque Nizamie, MD, DPMCentral Institute of PsychiatryKanke (PO)Ranchi 834 006 (India)Tel. +91 651 231844, ext. 212, Fax +91 651 233668, E-Mail jagpsy@yahoo.co.in ABC Fax +41 61 306 12 34E-Mail karger@karger.chwww.karger.com© 2003 S. Karger AG, Basel0302–282X/03/0472–0090$19.50/0Accessible online at:www.karger.com/nps Key Words Intravenous valproate W Loading therapy W Efficacy W Safety W Mania Abstract This open-label study investigated whether acute anti-manic effects and safety of intravenous valproate load-ing therapy is superior to oral valproate loading. Eight-een patients with DSM-IV diagnosis of either bipolaraffective disorder or schizomania who met the study cri-teria were recruited (9 in the intravenous and 9 in the oralvalproate group). Psychopathology was assessed withthe scale for manic and mixed states on days 0 and 4. Achecklist was used for the assessment of side effects. Theresults showed about 36% reduction in total mean manicscores with intravenous valproate loading; however, sta-tistically, the degree of reduction in manic scores wascomparable between the groups. A nonsignificant in-crease in the rate of adverse events was noted in theintravenous group. Despite its limitations, this study sug-gests that acute antimanic effects of both intravenousand oral valproate loading are comparable. Copyright © 2003 S. Karger AG, Basel Introduction Efficacy of sodium valproate (VPA) in the treatment of acute mania has been proven in controlled studies [1, 2].Although the intravenous form of VPA had been in usefor the treatment of epilepsy for the past several years,reports have only recently started describing its use in psy-chiatric conditions. For the first time, Erfurth and Grunze[3] have shown that intravenous VPA along with lamotri-gine were efficacious in treating acute mania. Simulta-neously, Hilty et al. [4] have reported that intravenousVPA is a safe and effective agent to achieve rapid controlover acute behavioral agitation in a child with autism.Later, a few more reports have also revealed acute anti-manic effects of intravenous VPA [5–10].Apart from rapid reduction of symptomatology, pa-tients who were previously unresponsive to oral VPAloading are also found to improve with intravenous VPAloading [3]. Pharmacokinetic profiles of intravenous load-ing, a quick saturation of plasma-binding proteins and arapid achievement of a peak of VPA concentration, whichis about 22% higher than that obtained with the equiva-lent oral dosage, have been the proposed reasons for itsbetter efficacy over oral VPA loading [5, 11]. Intravenous  Intravenous Valproate for Manic Symptoms Neuropsychobiology 2003;47:90–93 91 VPA loading is generally well tolerated, even by patientswith cardiovascular instability [12]. And, at present, in-travenous VPA loading is considered for patients withextreme symptoms requiring rapid control such as acutemania and agitation, and patients who have difficulty intolerating oral drugs either because of nausea or becausethey refuse to take them [13] and who have undergonegastric bypass surgery [7].Intravenous VPA loading dose of 20 mg/kg/day is gen-erally preferred, each dose being given over 60 min at theinfusion rate of 20 mg/min. VPA has to be diluted with atleast 50 ml of a compatible solution such as saline, 5%dextrose or lactated Ringer’s solution. Intravenous VPAcan be given at the same frequency as the oral product,but if the total daily dose exceeds 250 mg/day, it has to begiven in 2 or 3 separate doses [13]. Because the abovestudies on intravenous VPA loading have been casereports and due to our earlier experience with intravenousVPA loading therapy for manic symptoms in 2 patientswhich was encouraging [10], we undertook this prelimina-ry comparative study. It was aimed at examining theacute antimanic efficacy and safety of intravenous VPAloading in comparison with oral VPA loading. Methods This open-label study was conducted with inpatients of the Cen-tral Institute of Psychiatry, Ranchi, India, between June and August2001. Patients who were admitted to an adult male unit, with aDSM-IV [14] diagnosis of either manic episode (296.0x, 296.4x) orschizoaffective, bipolar type (295.70), aged 18–60 years, were en-rolled after getting their informed consent. The diagnoses were madeon the basis of detailed clinical interviews. Because of the prelimina-ry nature of this study, only those patients who had either clinicallyevident severe manic excitation and aggressive behaviors, poorresponse to other mood stabilizers, or poor tolerance to neurolepticswere included. Before starting the study, patients who were eligiblehad undergone detailed physical, psychiatric and laboratory (liverfunction test, platelet count and hemogram) examinations. Patientswith comorbid or underlying medical and neurological illnesses, sub-stance dependence other than nicotine, a low platelet count, and seri-ous risk of suicide were excluded. A strict washout period was notconsidered.Of the 18 patients who participated in this study, 9 were assignedto the intravenous VPA loading (intravenous group) and the rest tothe oral VPA loading (oral group) therapy. Assignment of patients toeither the intravenous or oral group was done depending upon theirwillingness (non-random assignment). In both groups, treatment wascommenced with VPA in doses of 20 mg/kg/day given in 2 separatedoses. Injection of VPA was diluted into 100 ml of intravenous fluid,either Ringer lactate or normal saline or 5% dextrose saline, and giv-en over a period of 1 h with the rate of infusion being 20 mg/min. Forresource constraints, we did not measure the serum VPA level. Noneof the subjects in either group received antipsychotic medication dur-ing the study period. One patient each in the intravenous and oralgroup had received trihexyphenidyl (2–4 mg/day) for extrapyramidalsymptoms that occurred due to haloperidol that had been givenbefore inclusion in this study. No other drug, except lorazepam (2–12mg/day), was allowed to manage insomnia, restlessness, irritability,aggression and hostility. As literature reviews suggested, most pa-tients showing response to intravenous VPA loading within 2–4 daysof treatment, a study period of 3 days was chosen for efficacy analy-sis. After 3 days, intravenous VPA was converted to the same dosesof oral VPA.Severity of psychopathology was rated with a 20-item scale formanic states [15], which covers both classical and mixed mania. Asingle rater who was not blind to the treatment rated psychopatholo-gy before starting treatment (day 0) and 3 days after treatment (day4). Adverse effects were examined daily with a checklist for adverseevents.Data analysis was done with the Statistical Package for SocialSciences (SPSS Win version 10.01). Group differences for samplecharacteristics, total manic scores on days 0 and 4 and degree of improvement as evidenced by the difference between total manicscores of days 0 and 4, and side effects were examined with Fisher’sexact test and Mann-Whitney U test. The significance level ( · ) wasset at 0.05 or less. Results Sample Characteristics Of the 18 patients, 1 patient had schizoaffective disor-der, a bipolar subtype (included in the intravenousgroup), and the rest had bipolar affective disorder withthe last episode being mania with or without psychoticfeatures. The groups were similar in age, marital status,education, past psychiatric history and family history of psychiatric illness. Similarly, no significant group differ-ences were seen for duration of illness, duration of currentepisode, history of prior treatment, and doses of VPA andlorazepam (table1).  Efficacy In comparison with the oral group, baseline total meanmanic scores were significantly high in the intravenousgroup (p = 0.015). There was no group difference in termsof ‘day 4’ total mean manic scores. A considerable reduc-tion in total mean manic scores was found in the intrave-nous group (about 36% from baseline score); however,statistically, both groups had a comparable degree of reduction of total manic scores (table2, fig.1). Safety Six patients of the intravenous group and 2 of the oralgroup had experienced at least one adverse effect duringtreatment (Fisher’s exact test, p = 0.08). Of the variousadverse effects of VPA, patients in the intravenous group  92 Neuropsychobiology 2003;47:90–93 Jagadheesan/Duggal/Gupta/Basu/Ranjan/Sandil/Akhtar/Nizamie Fig. 1. Group differences in mean manic scores. had nausea (n = 1), diarrhea (n = 1), pain abdomen (n = 2),bloated abdomen (n = 1), tremor (n = 1), rigidity (n = 1),drowsiness (n = 1) and panic-like experience (n = 1). Simi-larly, patients in the oral group also had complicationssuch as vomiting (n = 1), anorexia (n = 1), tremor (n = 2),dizziness (n = 1), nystagmus (n = 1) and headache (n = 1).Adverse effects usually appeared during the second day of treatment in both the intravenous (2.00 B 1.00) and oral(2.00 B 1.41) group. Discussion A clinically observable improvement generally occursbetween 1 and 4 days, and in most studies, it has beennoted within 2 days of intravenous VPA loading therapy[3, 5, 6, 9, 13]. Likewise, in the present study, about 36%reduction in total mean manic scores was seen at the endof 3 days of intravenous VPA therapy. However, the Table 1. Characteristics of the participantsIntravenousgroup (n = 9)Oral group(n = 9)p valueAge 1 , yearsMarital status 2 SingleMarriedEducation 1 , yearsPast psychiatric history 2 Family history 2 Duration of illness 1 , monthsEpisode duration 1 , weeksHistory of prior treatment 2 VPA dose 1 , mg/dayLorazepam dose 1 , mg/day28.44 B 8.505 (55.6)4 (44.4)9.67 B 6.06 (66.7)3 (33.3)109.77 B 39.277.83 B 6.904 (44.4)1,133.33 B 200.004.44 B 7.8624.83 B 8.516 (66.7)3 (33.3)8.89 B 4.206 (66.7)2 (22.2)93.68 B 40.2810.72 B 8.166 (66.7)1,033.33 B 132.292.67 B 5.860.197 (Z = –1.290)0.6670.796 (Z = –0.266)1.0000.6470.090 (Z = –1.683)0.241 (Z = –1.172)0.3950.390 (Z = –0.861)0.580 (Z = –0.553)Figures in parentheses are percentages. 1 Mann-Whitney U test. 2 Fisher’s exact test. Table 2. Group differences for mean scoresof manic rating scaleIntravenous(n = 9)Oral group(n = 9)Z 1 p valueTotal score on day 0Total score on day 4Difference in scores of days 0 and 444.22 B 7.7727.88 B 4.6816.33 B 8.86 34.44 B 5.6822.00 B 13.2812.44 B 9.532.431–1.547–0.8400.0150.1220.400 1 Mann-Whitney U test.  Intravenous Valproate for Manic Symptoms Neuropsychobiology 2003;47:90–93 93 degree of improvement found in the intravenous VPAgroup was not significantly different from that of the oralgroup. This finding suggests that in the acute manage-ment, efficacy of intravenous VPA loading may be similarto that of oral loading.Except local injection site pain, redness [16] and seda-tion [5], previous studies do not report any other adverseevent during intravenous VPA therapy [3, 6, 13, 17, 18].In contrast, 6 of 9 patients of the intravenous group in thepresent study had experienced at least one adverse event,which was comparatively higher than that in the oralgroup. Patients in both groups had adverse effects involv-ing gastrointestinal and nervous systems. Notably, 1 pa-tient experienced panic-like anxiety after the first dose of intravenous VPA loading. Adverse effects, however, werenot severe enough to warrant withdrawal of medication inany patient. We are unable to explain the reason for suchan increased frequency of adverse events in the intrave-nous group. Nevertheless, these findings underscore theneed for careful observation during intravenous VPAloading therapy.This is the first study to compare acute therapeutic effi-cacy and safety of intravenous VPA and oral VPA load-ing. Unlike earlier reports, antipsychotics and other moodstabilizers were not allowed during VPA loading. Thispreliminary study has a few shortcomings. Of them, themain limitation is the lack of measurement of serum VPAlevel, which could have indicated in which treatmentgroup the therapeutic level was achieved faster and towhat degree. Other limitations include the open-labeldesign, nonrandom sample assignment, the small samplesize and the lack of a pretreatment washout period.In sum, although a considerable reduction in manicsymptomatology ensued, this preliminary study has failedto confirm the superior acute antimanic efficacy of intra-venous VPA loading over oral loading. This finding sug-gests the need to identify clear indicators for intravenousVPA loading therapy. Further, because adverse effectsmay occur more often with intravenous therapy, regularmonitoring during treatment is indispensable. A double-blind study with a large sample size is necessary to con-firm acute antimanic efficacy of intravenous VPA loadingover other modes of acute intervention. References 1Pope HGJ, McElroy SL, Keck PE, Hudson JL:A placebo-controlled study of valproate in ma-nia. Arch Gen Psychiatry 1991;48:62–68.2Bowden CL, Brugger AM, Swann AC, Cala-brese JR, Janicak PG, Petty F, Dilsaver SC,Davis JM, Rush AJ, Small JG, Garza-TrevinoES, Risch SC, Goodnick PJ, Morris DD: Effi-cacy of divalproex vs lithium and placebo inthe treatment of mania. JAMA 1994;271:918–924.3Erfurth A, Grunze H: New perspectives in thetreatment of acute mania: A single case report.Prog Neuropsychopharmacol Biol Psychiatry1998;22:1053–1059.4Hilty DM, Rodriguez GD, Hales RE: Intrave-nous valproate for rapid stabilization of agita-tion in neuropsychiatric disorders. J Neuropsy-chiatry Clin Neurosci 1998;10:365–366.5Grunze H, Erfurth A, Amann B, Giupponi G,Kammerer E, Walden J: Intravenous valproateloading in acutely manic and depressed bipolarI patients. J Clin Psychopharmacol 1999;19:303–309.6Herbert PB, Nelson JC: Parenteral valproatefor control of acute mania. Am J Psychiatry2000;157:1023–1024.7Kaltsounis J, DeLeon OA: Intravenous val-proate treatment of severe manic symptomsafter gastric bypass surgery: A case report. Psy-chosomatics 2000;41:454–456.8Norton JW: The use of intravenous valproatein acute mania. Gen Hosp Psychiatry 2000;22:389–391.9Kahn SA, Thornton S: Use of intravenous val-proate for manic episodes. Med Psychiatry2001;4:11–15.10Duggal HS, Jagadheesan K, Gupta S, Basu S,Akhtar S, Nizamie SH: Intravenous valproate:A new perspective in the treatment of manicsymptoms. Indian J Psychiatry, in press.11Wangemann M, Wolf C, Retzow A: Replace-ment of oral valproate with intravenous val-proate: A study on dose finding and bioavail-ability. Eur J Clin Res 1997;9:209–215.12Sinha S, Naritoku DK: Intravenous valproateis well tolerated in unstable patients with statusepilepticus. Neurology 2000;55:722–724.13Norton JW, Quarles E: Intravenous valproatein neuropsychiatry. Pharmacotherapy 2000;20:88–92.14American Psychiatric Association: Diagnosticand Statistical Manual of Mental Disorders, ed4. Washington, American Psychiatric Associa-tion, 1994.15Cassidy F, Murray E, Forest K, Carroll BJ:Signs and symptoms of mania in pure andmixed episodes. J Affect Disord 1998;50:187–201.16Venkataraman V, Wheless JW: Safety of rapidintravenous infusion of valproate loading dosesin epilepsy patients. Epilepsy Res 1999;35:147–153.17Chez MG, Hammer MS, Loeffel M, Nowinski,Bagan BT: Clinical experience of three pediat-ric and one adult case of spike and wave statusepilepticus treated with injectable valproicacid. J Child Neurol 1999;14:239–249.18Limdi NA, Faught E: The safety of rapid val-proic acid infusion. Epilepsia 2000;41:1342–1345.
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