Kloza - The antipsychotic for treatment resistant schizophrenia

Kloza - The antipsychotic for treatment resistant schizophrenia

Why is clozapine (Kloza) prescribed?

Clozapine is used to treat the symptoms of schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or inappropriate emotions) in patients for whom other medicine has not worked or who are at risk of attempting suicide. Clozapine is in a class of medications called atypical antipsychotics. It works by changing the activity of certain natural substances in the brain.

Introduction

Clozapine (Kloza) is a di-benzodiazepine derivative and a truly atypical anti-psychotic. Its therapeutic effects are probably mediated by dopaminergic and serotonergic activity. Although it appears to be the most effective antipsychotic drug for treatment-resistant schizophrenia, its general use is limited because of the risk of agranulocytosis.Clozapine is manufactured by Reliance Formulation and marketed by the trade name of 'Kloza'.

Clozapine is an atypical anti-psychotic agent whose mode of action is thought to pertain to its interaction with dopaminergic and serotonergic neurotransmitter systems. Its clinical efficacy may depend on plasma clozapine concentrations; but its response rate varies widely. The response rate is anywhere between 30-100% of patients on short term therapy; while during long term treatment 60% of patients unresponsive to or intolerant of previous antipsychotics respond to clozapine. Significant improvements in both positive and negative psychotic symptoms, quality of life, social functioning and suicidality have been demonstrated.Clozapine represents the first major advance in the treatment of schizophrenia since the advent of antipsychotics in the1950's (Lieberman, 1996). Although Clozapine has been found to be the most effective antipsychotic drug for treatment-resistant schizophrenia, its use has been greatly limited because of the risk of agranulocytosis, which has in fact been shown to have a frequency that is less than 1%. (Honingfield G, 1996). In balancing benefits against risks it is worth noting that the suicide mortality rate in patients with schizophrenia not treated with clozapine is much higher than the mortality from agranulocytosis in the patients treated on clozapine. (Walker et al, 1997, Meltzer et al, 1995). With periodic blood monitoring, the agranulocytosis risk is 0.38% (Honigfield G, 1996).Background historyClozapine was introduced in Europe in 1975.As a result of reports from Finland, where 16 patients out of 2260 exposed (0.7%) developed agranulocytosis and 8 (50%) of them subsequently died from secondary infections, the drug was voluntarily withdrawn from use.Following pressure from psychiatrists to reintroduce clozapine, trials in patients with treatment resistant schizophrenia, under close haematological monitoring were devised, which showed significant improvement in 30% of patients after six months (Kane et al, 1988).

Subsequent studies showed improvement in 61% of patients if treatment was continued for up to one year (Meltzer et al, 1989; Meltzer, 1992). These data, together with a proposal for a national co-ordinated mandatory haematological monitoring service for all patients, enabled clozapine to be given a product licence in the UK in January 1990, and in Ireland in August 1993. Services (CPMS) ensuring that no patient can receive the drug without a recent satisfactory hematological result.

It also helps guarantee that clozapine is stopped immediately if a patient develops a fall in the white cell count. Since the introduction of the CPMS only one patient has died in UK as a direct result of clozapine-induced agranulocytosis. (Mangan and Toal, 1994). Despite its proven benefits, clozapine is probably under prescribed because of its limited indication of treatment-resistant and treatment-intolerant schizophrenia and the negative perception relating to the risk of agranulocytosis.

Indications:

Under the terms of its UK license clozapine should only be used for patients with schizophrenia who are unresponsive to two or more anti-psychotics or who are intolerant of their neurological side effects. Clozapine's beneficial use in several unlicensed disorders is being investigated, including psychosis secondary to dopaminergic therapy or coexisting psychiatric disorders in Parkinson's disease, other psychotic disorders, affective disorders, dyskinesias and related disorders, dementia, mental retardation, and polydipsia / hyponatraemia.There are a number of reports, showing its dramatically beneficial effect in the patients with severe personality disorder where all other treatment options failed. These case reports and small studies show marked reduction in self harming behaviour, aggression and intensive affective response in this patient group (Frankenburge et al, 1993;Steinert et al, 1995;Chengappa et al , 1995; Benedetti et al, 1998).There is evidence to suggest that, used in schizophrenia, clozapine may improve social functioning, occupational functioning and quality of life and that it may also reduce affective symptoms, hospitalization, secondary negative symptoms and tardive dyskinesia.

Pharmacology:

Clozapine is a prototype 'broad- spectrum' antagonist. Its binding profile is quite different from other anti-psychotics both within and outside the dopaminergic system. It has relatively low affinity for D2 receptors in the striatum, while its in vitro affinity for the D4 receptors is approximately 10 times greater than that for D2 receptors and it has also been shown to bind to the D1, D3 and D5 receptors. Since D4 density is highest in the frontal cortex and amygdala but relatively low in the basal ganglia, that may be the explanation for the efficacy of clozapine in alleviating the symptoms of schizophrenia without causing extra pyramidal side effects.Clozapine has been recognized to show significant activity at a broad range of receptors outside the DA system. Of particular interest is clozapine's high affinity for 5-HT receptors including 5-HT2, 5-HT3, 5-HT6 and 5-HT7 subtypes.

Clozapine has high affinity for a1, a2 and muscarinic receptors, while it also has significant effect on GABA-ergic and glutamatergic mechanisms.Pharmacokinetics and metabolismAfter oral administration the drug is rapidly absorbed. There is extensive first pass metabolism and only 27-50%of the dose reaches the systemic circulation unchanged.Clozapine's plasma concentration has been observed to vary from patient to patient. Various individual factors may vary response such as smoking, hepatic metabolism, gastric absorption, age, and possibly gender.Clozapine is rapidly distributed; it crosses the blood-brain barrier and is distributed in breast milk. It is 95% bound to plasma proteins. Steady state plasma concentration is reached after 7-10 days. The onset of anti-psychotic effect can take several weeks, but maximum effect may require several months. In treatment resistant schizophrenia, patients have been reported to continue to improve for at least two years after the start of clozapine treatment.

Clozapine metabolizes into various metabolites, out of which only norclozapine (desmethyl metabolite) is pharmacologically active. The other metabolites do not appear to have clinically significant activity.Its plasma concentration declines in the biphasic manner, typical of oral anti-psychotics and its mean elimination half-life ranges from 6-33 hours. About 50% of a dose is excreted in urine and 30% in the faeces.DoseClozapine is started from a dose of 12.5mg/day. On day two the dose can be increased to 12.5mg twice daily. If the patient is tolerating the clozapine, the dose can then be increased by 25mg to 50mg a day, until a dose of 300mg a day is reached. This can usually be achieved in two to three weeks.
Further dosage increases should be made slowly in increments of 50mg to 100mg each week. A dose of 450mg/day or a plasma level of 350mcg/L should be aimed for. The total clozapine dose should be divided and, if sedation is a problem, a larger proportion of dose can be given at night.
( Bethlem & Maudsley NHS Trust Prescribing Guidelines, 1999).

Therapeutic Efficacy:

The efficacy of clozapine has been examined in a large number of studies since it was first introduced.

There is a substantive number of randomised double blind trials, in which clinical efficacy of clozapine in acutely psychotic and treatment resistant schizophrenics has been rigorously examined.

Effect on Positive and Negative Symptoms of Schizophrenia:

Both positive and negative symptoms of schizophrenia appeared to be improved with clozapine treatment). Negative symptoms improve in direct relation to positive symptoms in 40 schizophrenic patients after clozapine therapy for eight weeks. (Tandon and Goldman et al, 1993).Lieberman et al; 1969, reported that negative symptoms responded to treatment approximately 7 weeks after decrease in positive symptoms in 84 patients with treatment-resistant schizophrenia. The results of these studies imply that the greater improvement in negative symptoms seen in patients receiving clozapine compared with those receiving classical anti-psychotic agents may be associated with the greater improvement in positive symptoms and fewer extra pyramidal symptoms (which can mimic negative symptoms) in these patients, rather than an independent action on negative symptoms (Breier; Buchanan et al; 1994). However, in a cohort of 36 patients with schizophrenia unresponsive to previous therapy, statistically significant reduction in Brief Psychiatric Rating Scale (BPRS) on withdrawal/retardation score were seen after six months' therapy with clozapine and psychosocial treatment in patients with high negative/low positive as well as in those with high negative/high positive symptoms (Meltzer et al;1995)

Acute PsychosisMost of the studies found clozapine to be more effective than conventional neuroleptics in treating both positive as well as negative symptoms in acutely ill schizophrenics (Ekblom and Haggstrom 1974, Singer and Law 1974, Chiu et al 1976, Gelenberg and Dollar 1979, Claghorn et al 1987).
Treatment resistant schizophreniaClozapine is still the only drug of proven efficacy in treatment resistant schizophrenia (Conley et al-1997, Weiden PJ et al- 1997). The significant response of neuroleptic- resistant schizophrenia patients to clozapine validates its efficacy in this group (Baldessarini et al-1991).Kane et al 1988 in their famous multicentre double-blind trial compared chlorpromazine with clozapine in equivalent doses and found that 4% chlorpromazine vs. 30% clozapine group responded by marked reduction in BPRS score (both positive and negative symptoms) in 6 weeks.

Lieberman et al reported that the response rate of clozapine was 50% among previously treatment- refractory patients and 76% among treatment-intolerant patients.

Objective measures have indicated a marked improvement in psychopathology, including negative symptoms such as blunted affect, emotional withdrawal and apathy. (UK clozapine study group-1993, Breier et al-1994). Besides improvement of positive and negative symptoms, clozapine may improve organization of thought, certain aspects of cognitive function and enable patients to resume functioning in a low normal range. (Meltzer HY-1992)
In line with an improvement in overall psychopathology, treatment with clozapine is associated with improved compliance with medication regimen and less need for hospitalisation (Meltzer HY-1992, Arnon et al-1995, Grace et al- 1996).Effect of clozapine on aggressive behaviourThe improvement in aggressive behaviour among schizophrenic patients receiving clozapine has been an interesting finding in the clinical trials. (Maier et al- 1992, Wilson-1992, Volavka et al-1993, Chiles et al- 1994, Ebrahim et al-1994, Buckley- 1995Spivak B et al- 1997).
Question arises whether clozapine's efficacy derives from a specific antiaggressive effect or, the reduction in violent behaviour merely reflects an overall improvement in psychosis. Buckley et al have addressed this issue by comparing the symptomatic response to clozapine in 30 institutionalized schizophrenic patients, 11 of whom displayed persistent violent behaviour before initial use of clozapine. Although the violent patients showed a dramatic reduction in aggression during 6 months of clozapine treatment, their overall response to measures on BPRS was comparable to that of nonviolent patients.
This suggests that violent behaviour was not tightly coupled to severity of illness per se and raises the possibility of a distinct antiaggressive effect. Volavka et al-1993 in New York have also demonstrated a selective effect of clozapine on hostility that is above and beyond the improvement of psychosis.It is presently uncertain how clozapine could be incorporated in the pharmacological treatment of aggression. Its side effects limit its broad use for patients of varying conditions and severity who also exhibit violent behaviour. If the violence was a severe problem however, the benefit could outweigh the potential risk.
Drug and Alcohol abuseClozapine significantly decreases co-morbid use of alcohol and drugs in people with schizophrenia, possibly by reduction in craving (Harvard review of Psychiatry,1999)(Albanese et al-1994)(Frankenburg FR-1994). In one case study, a decrease in cocaine use after clozapine therapy was reported in a treatment resistant 37 year old man with schizoaffective disorder (Yovell - 1994). There are other reports of dramatic cessation of substance abuse, attenuated craving, and improved psychosocial functioning during clozapine therapy (Buckley -1998). Patients report reduction in craving, which has been considered to be due to the differential effect of clozapine on dopamine neurotransmission in nucleus accumbens, a region known to be involved in the neurobiology of craving.Prevention of SuicideEvidence is accumulating that clozapine is efficacious in reducing suicidality in schizophrenia. Meltzer, (1999) in the Clozapine and InterSepT study reported a 80-85% reduction in the incidence of suicide in neuroleptic resistant patients on clozapine. Walker et al (1997) reported the results of a retrospective analysis of mortality of 67,072 schizophrenic patients receiving clozapine in the interval between April 1 ,1991 and December 31, 1993. The data were acquired from the Kloza national registry. Patients were classified as current, recent, or past clozapine users. The striking finding was that of a dramatic reduction in the incidence of suicide among current users of clozapine. While the incidence of suicide in this cohort was 19% of overall mortality, the patients who completed suicide were primarily those who had stopped using clozapine.Mood DisordersClozapine has been shown to be effective in severe mood disorders. In a 1-year randomized trial of clozapine versus treatment-as- usual among 39 bipolar patients, clozapine’s superiority was evident within the first 6 months of treatment and was maintained throughout the duration of this study. (Suppes, Rush, et al - 1996). Zarate et al-1995 reported that, for schizoaffective disorder, 70% of patients achieved demonstrable improvement in symptoms with clozapine therapy. Clozapine has also been reported to be of benefit in psychotic depression. (McElroy SL-1991).Drug induced psychosis in Parkinson's DiseaseA randomised, double blind, placebo controlled trial of low doses of clozapine (25 to 50mg per day) in 60 patients over a period of 14 months showed significant improvement in drug induced psychosis in Parkinson's disease, without worsening Parkinsonism (The Parkinson Study Group, 1999).Borderline personality disorderIndividual case reports and small studies have shown clozapine to be effective in the treatment of resistant cases of borderline personality disorder in reducing self harm, aggressive behaviour and other associated symptoms. (Frankenburge et al, 1993; Steinert et al, 1995; Chengappa et al, 1995 ; Benedetti et al, 1998).Economic considerationsA full appraisal of the pharmacological benefits and costs associated with clozapine in the treatment of schizophrenia has been provided by Fitton and Benfield (Fitton and Benfield, 1993). When inpatient and outpatient care, Residential care, Community- based services, drug therapy, and lost productivity and earnings are taken into consideration, it may be readily understood that schizophrenia places a major economical burden in society. The direct annual treatment cost of schizophrenia in the UK is estimated to be £1669 per person, comprising hospital inpatient care (£572), other residential care (£662), outpatient visits (£56), day care (£228), community work, social work, general practitioner fees (£63), depot injection clinic (£32) and drug therapy.(£56); 3.4% of total cost. Indirect costs associated with schizophrenia include morbidity, morality, productive losses borne by relatives, and administration costs incurred by the community relating to criminal justice and social welfare. The overall cost of untreated aggression and violence within the health care system and on society is difficult to estimate. Affective treatment of psychotic symptoms and associated aggression can bring the total cost down considerably.

Cautions and contra indications:

1-Patients with myeloproliferative disorders, a history of of toxic or idiosyncratic agranulocytosis or severe granulocytopenia (with the exception of granulocytopenia/ agranulocytosis from previous chemotherapy)

2-Clozapine is contraindicated in patients with active liver disease, progressive liver disease and hepatic failure.

3-Other contraindications include severe CNS depression or comatose state, severe renal and cardiac disease, uncontrolled epilepsy, circulatory collapse, alcoholic/toxic psychosis and previous hypersensitivity to clozapine.

Side effects:

The most serious of clozapine's side effects is agranulocytosis. Other important side effects include postural hypotension and tachycardia, sedation, seizures, weight gain, and rebound psychosis.Clozapine can also cause:
Nausea,vomiting and constipation.

Elevation of liver enzymes (frequency up to 10%)
Hypersalivation (frequency 12-40%)
Confusion or delirium
Incontinence frequency/urgency, hesitancy, urinary retention, or impotence (6%)
Benign hyperthermia (5-15%)

Development or exacerbation of obssesive compulsive symptoms (Baker et al, 1992; Patil, 1992; Meltzer, 1993)

Interactions:

1-Drugs that cause CNS depression, if used concomitantly with clozapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and possibly respiratory depression. Ethanol and drugs like, histamine blockers, benzodiazepines, opiate agonists, sedative-hypnotics and tricyclic antidepressants should be used with caution.

2-Concomitant use of drugs known to cause bone marrow depression might increase the possibility of developing myelosuppressive effects.

3-Clozapine has marked anticholinergic activity, and concurrent use with other anticholinergic drugs can increase side effects such as dry mouth, constipation, loss of accommodation, and urinary retention.

4-Carbamazepine, phenytoin and other cytochrome P-450 enzyme inducers can reduce clozapine plasma concentration, Clozapine in turn can increase the serum concentration of of the following drugs; digoxin, heparin, phenytoin, and warfarin.

5-Drugs such as erythromycin, Cimetidine fluoxetine or fluvoxamine, can inhibit cytochrome P-450 metabolism and can increase clozapine plasma concentration.

6-Clozapine used concomitantly with other antihypertensive agents can increase the risk and severity of hypotension.7- Clozapine used in combination with Lithium can increase the risk of developing seizures, confusion, dyskinesia, and possibly, neuroleptic malignant syndrome.

Conclusions:

In terms of efficacy against conventional treatment-resistant schizophrenia, clozapine (Kloza) remains an unparalleled choice although its general use is limited because of the risk of agranulocytosis.

References
Avnon M. et al, 1996 Effectiveness of clozapine in hospitalized people with chronic schizophrenia, Br J Psychiatry; 167: 760-764.Breier A, Buchanan RW, Kirkpatric B,et al, 1994 Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry; 151: 20-Buckley PF ; 1996, Treatment of schizophrenia; some advances in the decade of brain. Br J Hosp Med;, 56, 575-581Buckley PF, Kausch O, Gardener G; 1995, Clozapine treatment of schizophrenia: implication for forensic psychiatry. J Clin Forensic Med.; 2: 6-16.Buckley P, 1995 Bartell J, et al; Violence and schizophrenia: clozapine as specific antiaggressive agent. Bull Am Acad Psychiatry Law; 23: 607-611Bell R, 1998 The clinical use of plasma clozapine levels, (review) Australian & NewZealand Journal of Psychiatry.32(4);567-74, Aug.Benedetti et al, 1998; Low dose clozapine in acute and continuation treatment of severe Borderline Personality Disorder. J Clinical Psychiatry; 59,103-7.Breier, Buchanan, Kirkpatrick et al. Jan, 1994; Effects of clozapine on positive and negaive symptoms in outpatients with schyzophrenia. Am J Psychiatry; 151; 20- 6.Clozapine Study Group: 1993; The safety and efficacy of clozapine in severe treatment-resistant schizophrenic patients in U.K. Br J Psychiatry 150-154Carpenter WT, Conley RR, Buchnan RW. et al; 1995,Patient response and resourse management: Another view of of clozapine treatment of schizophrenia. Am J Psychiatry; 152: 827-832.Chengappa et al; 1995 The successful use of clozapine in ameliorating severe self-mutilation in a patient with Borderline Personality Disorder, Journal of Personality Disorder; vol. 9. Davies L.M. Drummond M.F, 1990; The economic burden of schizophrenia;. Psychiat Bull 14; 522-5.FittonA. Benfield P. August, 1993; Clozapine and its pharmacoeconomic benefits in the treatment of schizophrenia. Pharmaco Economics; 31- 56.Frankenburge and Zanarini; Nov/Dec, 1993; Comprehensive Psychiatry, 34(6).Harvard review of Psychiatry, 1999 Mar-Apr ( Green AL et al) Clozapine for comorbid substance use disorder and schizophrenia; do patients with schizophrenia have a reward-deficiency syndrome that can be ameliorated by clozapine?. 6(6);287-96, Kane J, Honigfield G, Singer J, et al: 1989 Clozapine for the treatment-resistant schizophrenic; result of a US multicentre trial, Psychopharmocology ;; 99, 560-563Kane J, Honigfield G, Singer J, et al: 1988 Clozapine for the treatment-resistant schizophrenic; a double blind comparison with chlorpromazine (Kloza collaborative study). Arch. Gen. Psychiatry;, 45; 789-796Kerwin JR. Taylor D; 1996; New antipsychotics a review of their current status and clinical potential. Drugs 6. 71-82Lindstrom LH, 1989 A retrospective study on the long-term efficacy of clozapine in 96 schizophrenic and schizo-effective patients during a 13-year period. Psychopharmacol.; 99; 84-86Lieberman JA, Safferman AZ, Pollack S, et al; 1994; Clinical effects of clozapine in chronic schizophrenia: response to treatment and predictors of outcome. Am J Psychiatry 151:1744-1752.Meltzer HY et al; 1990 Effects of six months clozapine treatment on the quality of life of chronic schizophrenic patients, Hosp Comm Psychiatry; 41: 892-897.Meltzer HY et al; 1995 Clozapine; is another view valid? Am J psychiatry; 152 (6); 821-5.Marcus P, Snyder R; 1994; Reduction of comorbid substance abuse with clozapine. Am J Psychiatry 151:959.McElroy SL, et al; 1991 Clozapine in the treatment of psychotic mood disorders, schizoeffective disorder and schizophrenia.J Clin Psychiatry; 52; 411-414.Meltzer HY, 1999.Suicide and Schizophrenia; clozapine and the InterSept study, Journal of Clinical Psychiatry. 60 Suppl 12; 47-50, Suppes T, Rush AJ, Web A et al: 1996; A one year randomized trial of clozapine v's usual care in Bipolar I patients, Biol Psychiatry 39:531.Spivak B, Mester R, et al; 1997; Reduction of aggressiveness and impulsiveness during clozapine treatment in chronic treatment resistant schizophrenic patients. Clin Neuropharmacol 20: 442-446.Steinert et al; 1996. A case report, Pharmacopsychiat.29; 111-114, Tandon and Goldman et al;. Oct- Dec, 1993; Positive and negative symptom, during clopazine treatment in schyzophrenia. J Psychiatry Res;; 341- 7.The Parkinson's Study Group; 1999; Low dose clozapine for the treatment of drug induced psychosis in Parkinson's Disease; N Engl J Med. 340, 757-63Volavka J, 1999.The effect of clozapine on aggression and substance abuse in schizophrenic patients, (Review) Journal of Clinical Psychiatry. 60 Suppl 12; 43-6, -Volavka et al; 1993; Clozapine effects on hostility and aggression in schizophrenia. J Clin Psychopharmacol. 13; 287-289Walker et al; 1997 Mortality in current and former users of clozapine. Epidemiology; 8; 671-677.Zarate et al; 1995; Clozapine in severe mood disorder, J Clin Psychiatry 56: 411-417.

For further details, please e-mail to:

Mr. Mukesh Vankani - General Manager

or

Mr. Deepak Shah - B.Pharma, MBA

at

reliancehealthcare@yahoo.co.in

Apiz: Product Information

Apiz - Product Information

Pharmacology

Aripiprazole possesses a novel mechanism of action when compared to the other FDA approved atypical antipsychotics. Aripiprazole appears to mediate its antipsychotic effects primarily by partial agonism at the D2 receptor. Partial agonism at D2 receptors has been shown to modulate dopaminergic activity in areas where dopamine activity may be high or low, such as the mesolimbic and mesocortical areas of the schizophrenic brain, respectively. In addition to partial agonist activity at the D2 receptor, aripiprazole is also a partial agonist at the 5-HT1A receptor, and like the other atypical antipsychotics, aripiprazole displays an antagonist profile at the 5-HT2A receptor. Aripiprazole has moderate affinity for histamine and alpha adrenergic receptors, and no appreciable affinity for cholinergic muscarinic receptors.

Pharmacokinetics

Aripiprazole displays linear kinetics with an elimination half-life of approximately 75 hours. Accordingly, steady state plasma concentrations are achieved in about 14 days. Cmax (maximum plasma concentration) is achieved in 3-5 hours after oral dosing. The bioavailabilty of the oral tablets is about 90%. The drug undergoes extensive hepatic metabolization (dehydrogenation, hydroxylation, and N-dealkylation). The active major metabolite is dehydro-aripiprazole with an elemination half-life of about 94 hours. The parent drug is excreted only in traces and the metabolites, whether active or not, are excreted via feces and urine.

Metabolism

Aripiprazole is metabolized by the cytochrome P450 isoenzymes 3A4 and 2D6. Accordingly, coadministration of aripiprazole with medications that may inhibit (e.g paroxetine, fluoxetined) or induce (e.g. carbamazepine) these metabolic enzymes may increase or decrease, respectively, plasma concentrations of aripiprazole

Adverse events

Adverse events reported in the package insert for aripiprazole include headache, nausea, vomiting, somnolence, insomnia and akathisia. It appears that aripiprazole has a very low incidence of EPS (extrapyramidal side effects). The risk of tardive dyskinesia with prolonged aripiprazole use is unclear.

Dosage forms

Apiz is available as 10 and 15 mg tablets.

Dosage:

10 -15mg per day or as directed by physician. It has been observed that increasing the dose beyond 15 mg per dayb does not impart any particular therapeutic benefit. On the other hand, it may only add to the cost of treatment.


Warning about drugs having similar names

A warning has gone out recently because of this drug's name. The '-prazole' ending of this drug name makes this drug sound like it is one of the proton pump inhibitors (such as omeprazole, pantoprazole, lansoprazole) which are used in treating peptic ulcer disease. However, aripiprazole and these drugs are in an entirely different class of drugs altogether and confusing the two can lead to some unnecessary side effects.

Why is aripiprazole prescribed?

Aripiprazole is used to treat the symptoms of schizophrenia (a mental illness that causes disturbed or unusual thinking, loss of interest in life, and strong or inappropriate emotions). It is also used to treat episodes of mania (frenzied, abnormally excited or irritated mood) or mixed episodes (symptoms of mania and depression that happen together) in patients with bipolar I disorder (manic depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Aripiprazole is in a class of medications called atypical antipsychotics. It works by changing the activity of certain natural substances in the brain.

How should this medicine be used?

Aripiprazole comes as a tablet to be taken by mouth. It is usually taken once a day with or without food. Take aripiprazole at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take aripiprazole exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Your doctor may start you on a low dose of aripiprazole and increase your dose after at least 2 weeks.

Aripiprazole controls schizophrenia but does not cure it. It may take 2 weeks or longer before you feel the full benefit of aripiprazole. Continue to take aripiprazole even if you feel well. Do not stop taking aripiprazole without talking to your doctor.

What special precautions should I follow?
Before taking aripiprazole,
tell your doctor and pharmacist if you are allergic to aripiprazole or any other medications. Tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking. Be sure to mention any of the following: amiodarone (Cordarone, Pacerone); antidepressants (mood elevators); antifungals such as fluconazole (Diflucan), itraconazole (Sporanox), and ketoconazole (Nizoral); antihistamines; bupropion (Wellbutrin); carbamazepine (Tegretol); celecoxib (Celebrex); chlorpromazine (Thorazine); cimetidine (Tagamet); clarithromycin (Biaxin); clomipramine (Anafranil); cyclosporine (Neoral, Sandimmune); danazol (Danocrine); delavirdine (Rescriptor); dexamethasone (Decadron); diltiazem (Cardizem, Dilacor, Tiazac); doxorubicin (Adriamycin); erythromycin (E.E.S., E-Mycin, Erythrocin); ethosuximide (Zarontin); fluoxetine (Prozac, Sarafem); fluvoxamine (Luvox); HIV protease inhibitors such as indinavir (Crixivan) and ritonavir (Norvir); ipratropium (Atrovent); isoniazid (INH, Nydrazid); medications for anxiety, blood pressure, irritable bowel disease, mental illness, motion sickness, Parkinson's disease, seizures, ulcers, or urinary problems; metoclopramide (Reglan); methadone (Dolophine); metronidazole (Flagyl); nefazodone (Serzone); oral contraceptives (birth control pills); paroxetine (Paxil); phenobarbital (Luminal, Solfoton); phenytoin (Dilantin); primidone (Mysoline); quinidine (Cardioquin, Quinaglute, Quinidex); ranitidine (Zantac); rifabutin (Mycobutin); rifampin (Rifadin, Rimactane); sedatives; sertraline (Zoloft); sleeping pills; terbinafine (Lamisil); tranquilizers; troglitazone (Rezulin); troleandomycin (TAO); verapamil (Calan, Covera, Isoptin, Verelan); and zafirlukast (Accolate). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
tell your doctor if you have or have ever had heart disease, heart failure, high or low blood pressure, a stroke, a ministroke, seizures, Alzheimer's disease, any condition that makes it difficult for you to swallow, or if you or anyone in your family has or has ever had diabetes. Also tell your doctor if you have ever had to stop taking a medication for mental illness because of severe side effects.
tell your doctor if you are pregnant or plan to become pregnant. If you become pregnant while taking aripiprazole, call your doctor. Do not breastfeed while taking aripiprazole. If you are having surgery, including dental surgery, tell the doctor or dentist that you are taking aripiprazole.

you should know that aripiprazole may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
remember that alcohol can add to the drowsiness caused by this medication. Do not drink alcohol while taking aripiprazole.

you should know that you may have increases in your blood sugar (hyperglycemia) while you are taking this medication, even if you do not already have diabetes. If you have schizophrenia, you are more likely to develop diabetes than people who do not have schizophrenia, and taking aripiprazole or similar medications may increase this risk. Tell your doctor immediately if you have any of the following symptoms while you are taking aripiprazole: extreme thirst, frequent urination, extreme hunger, blurred vision, or weakness. It is very important to call your doctor as soon as you have any of these symptoms, because high blood sugar can cause more serious symptoms, such as dry mouth, upset stomach and vomiting, shortness of breath, breath that smells fruity, or decreased consciousness, and may become life-threatening if it is not treated at an early stage.

you should know that aripiprazole may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. This is more common when you first start taking aripiprazole. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
you should know that aripiprazole may make it harder for your body to cool down when it gets very hot. Tell your doctor if you plan to do vigorous exercise or be exposed to extreme heat. Make sure to drink plenty of fluids.

What special dietary instructions should I follow?

Talk to your doctor about drinking grapefruit juice while taking this medicine.
What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.
What side effects can this medication cause?

Aripiprazole may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• headache
• nervousness
• difficulty falling asleep or staying asleep
• drowsiness
• lightheadedness
• restlessness
• upset stomach
• vomiting
• constipation
• increased salivation
• weight gain
• coughing
• runny nose
• shaking hands that you cannot control
• dry skin
• itchy eyes
• loss of appetite
  

Some side effects can be serious. The following symptoms are uncommon, but if you experience any of them or those listed in the SPECIAL PRECAUTIONS section, call your doctor immediately:

• rash
• dizziness
• fainting
• slow, fast, or irregular heartbeat
• chest pain
• swelling of hands, feet, ankles, or lower legs
• depression
• seizures
• difficulty swallowing
• unusual movements of your body or face that you cannot control
• urgent need to urinate
• high fever
• muscle stiffness
• confusion
• sweating
• abnormal excitement
  

Aripiprazole may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

For further information on Apiz, please write to:
Mr. Mukesh Vanakani – General Manager
Or
Mr. Deepak Shah B.Pharma. MBA
At

reliancehealthcare@yahoo.co.in

Apiz - Summary of Clinical Trials on Aripiprazole

Apiz - Summary of Clinical Trials on Aripiprazole
GENERIC NAME: aripiprazole

BRAND NAME: Apiz (Reliance Formulation)

DRUG CLASS AND MECHANISM:

Aripiprazole is an anti-psychotic drug for treating psychoses. Like other anti-psychotic drugs, the mechanism of action of aripiprazole is unknown. Moreover, like other anti-psychotics, it blocks several receptors on the nerves of the brain for several neurotransmitters (chemicals that nerves use to communicate with each other). It is thought that its beneficial effect is due to its effects on dopamine and serotonin receptors. Its effects on these receptors are complex, involving stimulation of the receptors but to a lesser degree than the naturally occurring neurotransmitters (a process called partial agonism). The FDA approved aripiprazole as a treatment for schizophrenia in November of 2002.
---------------------------------------------------------------------------------------------------------------------------------------
1]
ARIPIPRAZOLE (Apiz):

Emerging as Next Great Hope for Schizophrenia

Editor's note: My son was diagnosed with schizophrenia in 1999 at the age of eighteen. We tried risperidone, ziprasidone, quetiapine, and clozapine without success or reduction of voices and symptoms, in fact, things just got worse. In December 2002, he switched to aripiprazole. Almost immediately there was a dramatic improvement, which has continued until today. Now he is more independent, has a renewed interest in life, has returned to college, and has an active social life. Things that previously were beyond our wildest hopes are now routine for him. Do not give up the search for something that works, every patient is unique! (June 2004)

Aripiprazole is being touted as the first member of the new generation of atypical antipsychotic drugs. This once-daily novel antipsychotic has undergone a number of studies, revealing that aripiprazole is significantly better at controlling both the positive and negative symptoms of schizophrenia than placebo and has equaled haloperidol and risperidone in its ability to control these symptoms.

On October 31, 2001, Bristol-Myers Squibb and Otsuka Pharmaceutical Co. filed a New Drug Application (NDA) with the FDA and the two companies anticipate the launch of aripiprazole late in the third quarter of 2002.

Stephen M. Stahl, M.D., Ph.D., Professor of Psychiatry at the University of California at San Diego, places aripiprazole in the class of antipsychotics called dopamine system stabilizers (DSSs). Stahl dubs these new therapeutic agents “Goldilocks” because of their ability to strike a balance between too much and too little dopamine. With “just right” result, negative and cognitive symptoms are reduced and motor side effects or prolactin elevation is absent.
Previous atypical drugs block dopamine D2 receptors resulting in motor side effects such as pseudo-parkinsonism, and ultimately tardive dyskinesia.

Robert McQuade, Ph.D., director of Global Medical Marketing for Bristol-Myers Squibb, cites the evolution of antipsychotic medications and how their mechanisms of action have changed over time. “The big disadvantage was the side effects,” he says. “The atypicals were designed to address symptoms such as EPS, but brought about different side effects.” Each drug within the atypical category elicited its own particular adverse event, according to McQuade. Literature suggests, he says, that olanzapine causes weight gain, ziprasidone increases the QTc interval and risperidone increases plasma prolactin.

“These drugs solved some problems, but created others.” “From a psychopharmacologic viewpoint, aripiprazole is bringing new science to the field,” he says. Unlike the older atypical antipsychotics that reduce positive symptoms of psychosis, such as delusions and hallucinations, by blocking D2 receptors, aripiprazole stabilizes or modulates them. McQuade underscores the multi-faceted benefits of aripiprazole based on the results of several controlled trials, some of which lasted up to 52 weeks in duration, involving more than 3,400 patients with schizophrenia. Aripiprazole was statistically superior to placebo on positive and negative symptoms and superior to haloperidol for negative symptoms, according to McQuade. “Aripiprazole delivers a package of tolerability that enhances the benefit to the patient and thus enhances compliance,” he concludes.
Potential problem with akathisia

According to Larry Ereshefsky, Pharm.D., professor of pharmacy, pharmacology and psychiatry at the University of Texas Health Science Center at San Antonio, the novel partial dopamine agonist mechanism of action augments the 5-Htla and 5-HT2 effects of aripiprazole. “These effects should lead to greater dopaminergic throughput and cortical activity which is good for thinking,” says Ereshefsky. “But it also might possibly explain the increased rates of akathisia at the middle doses (15 mg/d) in some studies. There is clearly a greater effect on the Barnes akathisia scale than from risperidone, and about half the effect of haloperidol.” Ereshefsy adds, “Akathisia is a potential side effect which bares further evaluation in long-term studies to see whether it abates.”
(Akathisia is having a feeling of inner restlessness and the urge to move, rocking while standing or sitting, lifting of the feet as if marching on the spot, and crossing and uncrossing of the legs while sitting)

---------------------------------------------------------------------------------------------------------------------------------------
2]

Title: New Antipsychotic Aripiprazole Shows Promise for Acute Mania: Presented at APA
"New Antipsychotic Aripiprazole Shows Promise for Acute Mania: Presented at APA"

By Alison Palkhivala PHILADELPHIA, PA -- May 23, 2002 --

Aripiprazole, a new investigational antipsychotic drug, is showing promise for the treatment of acute mania in patients with bipolar disorder. Studies on the drug were presented here this week at the annual meeting of the American Psychiatric Association (APA). As part of a phase III, multicenter, double-blind, randomized, placebo-controlled trial, 262 patients diagnosed with acute mania were treated with either aripiprazole or placebo. The study's lead author was Paul E. Keck Jr., MD, from the department of psychiatry at the University of Cincinnati College of Medicine in Cincinnati, Ohio. On day 4, patients in the treatment group began to show more improvement than the placebo group with respect to acute manic symptoms. These included elevated mood, irritability, thought disorder, abnormal thought content, and disruptive-aggressive behavior. A significant difference was also found between the two groups with respect to mean change from baseline on the total score of the Young Mania Rating Scale (Y-MRS), with the aripiprazole group showing more improvement than the placebo group. This difference increased as the three-week trial progressed. Response to therapy was defined as a decrease of 50 percent or more in Y-MRS total score. Based on this criterion, 40 percent of patients on aripiprazole responded to treatment compared to 19 percent on placebo. A second placebo-controlled study of aripiprazole did not reveal a difference between the drug and a placebo with respect to response rate. However, response rate in the placebo group was abnormally high: both the treatment and placebo groups had response rates of 40 percent. The most common side effects associated with aripiprazole therapy were headache, nausea, dyspepsia, somnolence, and agitation. Most side effects began early in treatment and few lasted more than a week. Aripiprazole has a mechanism of action that is different from other antipsychotic drugs, affecting both dopamine and serotonin receptors. It is the product of a cooperative effort between Bristol-Myers Squibb and Otsuka Pharmaceuticals. Together, they filed a regulatory applications in the US and Europe in 2001 for the drug to be approved for the treatment of schizophrenia.

---------------------------------------------------------------------------------------------------------------------------------------

3]

Title: Aripiprazole for Long-Term Maintenance Treatment in Schizophrenia: Presented at APA

"Aripiprazole for Long-Term Maintenance Treatment in Schizophrenia: Presented at APA"
By Bruce Sylvester PHILADELPHIA, PA -- May 23, 2002 --

The investigative antipsychotic drug aripiprazole produced improvements in positive, negative and depressive symptoms of schizophrenia during a 52-week study, researchers reported at the annual meeting of the American Psychiatric Association (APA). "Beyond the short-term clinical trials that have demonstrated acute efficacy, this study looks at aripiprazole in more long-term or maintenance treatment for schizophrenia. This is a chronic disorder with frequent relapses. In this study we looked at patients having acute relapses of their illness, at their stabilization with aripiprazole and then maintenance of the efficacy of the effect of this treatment over a one-year period," said Mary J. Kujawa, MD, medical director of US neuroscience medical affairs at Bristol-Myers Squibb Company in Princeton, New Jersey. The mechanism of action of aripiprazole appears to be different from other available antipsychotics. Aripiprazole shows potent partial agonism of D2 dopamine receptors, partial agonism of 5HT1A serotonin receptors and antagonism of 5HT2A serotonin receptors. Partial agonism means that aripiprazole blocks the receptor if it is overstimulated and stimulates it if it when activity is needed. The investigators in this multicenter, randomized, double-blind study recruited 1,294 subjects suffering an acute relapse of chronic schizophrenia. They randomized 861subjects to aripiprazole 30 mg/day and 433 to haloperidol 10 mg/day. They allowed a one-time dose reduction to aripiprazole 20 mg/day and haloperidol 7 mg/day. The investigators used Positive and Negative Symptoms for Schizophrenia (PANSS) and the Montgomery-Asberg Depression Rating Scale (MADRS) scores to evaluate efficacy throughout the study. Compared to the haloperidol cohort, a much larger percentage of patients treated with aripiprazole showed a therapeutic response and remained in treatment at weeks 8, 26, and 52 (week 52: 40 percent vs. 27 percent, p<0.001). Compared to haloperidol, aripiprazole elicited statistically significant improvements in the PANSS negative subscale and in depressive symptoms as shown in the MADRS. Extrapyramidal effect-related adverse events were significantly lower with aripiprazole than with haloperidol (p<0.001). Weight gain was comparable in both groups of subjects. QTc interval were also comparable between the groups. "One of the most difficult challenges in treating patients with schizophrenia is long-term adherence," said Jeffrey Lieberman, MD, professor of psychiatry and pharmacology at the University of North Carolina Medical School in Chapel Hill. "Data from this study suggests the potential for significant benefits of aripiprazole in the long-term treatment of schizophrenia, a chronic mental illness that affects approximately 1 percent of the world's population."

---------------------------------------------------------------------------------------------------------------------------------------4]
Title: Switching to Aripiprazole Safe and Effective in Schizophrenia: Presented at APA
By Alison Palkhivala PHILADELPHIA, PA -- May 23, 2002 --

Switching schizophrenic patients to new antipsychotic aripiprazole from both conventional and atypical antipsychotics appears to be both safe and well tolerated. For the study, 311 stable schizophrenic patients taking olanzapine, risperidone, or haloperidol were switched to aripiprazole using one of three switching strategies. These strategies consisted of a switch to a full dose of aripiprazole without titration from prior antipsychotic treatment, switching to a full dose of aripiprazole along with tapering of the previous treatment for two weeks, or switching to aripiprazole with titration up along with titration down of the previous medication over two weeks. The study was led by Daniel E. Casey, MD, from the Mental Illness Research, Education, and Clinical Center of the Portland Veterans Affairs Medical Center in Oregon. The study was presented here this week at the annual meeting of the American Psychiatric Association (APA). Regardless of the switching strategy employed, the switching process was generally safe and well tolerated. Eight weeks after switching to aripiprazole, patients showed improvements in extrapyramidal symptoms (EPS) and reductions in prolactin levels and weight. They also showed statistically significant improvements in the Positive and Negative Syndrome Scale (PANSS). Patients switched from olanzapine showed a statistically significant weight loss of 2.03 kg (p<0.001) as well as a decrease in prolactin levels and improvement in EPS. Those switched from risperidone also had statistically significant decreases in prolactin levels (p<0.001), as well as reductions in weight and EPS. Those switched from haloperidol had improvements in EPS and decreased prolactin levels. Aripiprazole was generally well-tolerated, with the most common side effect being insomnia. Most side effects were mild to moderate. Aripiprazole, a novel antipsychotic, is jointly produced by Bristol-Myers Squibb and Otsuka Pharmaceuticals. In 2001, they submitted the drug for approval to regulatory agencies in the United States and Europe.

---------------------------------------------------------------------------------------------------------------------------------------5]

Title: Aripiprazole Versus Placebo in the Treatment of Chronic Schizophrenia: Presented at APA
By Bruce Sylvester PHILADELPHIA, PA -- May 23, 2002 --

The investigative drug aripiprazole provides effective and safe antipsychotic treatment in patients with chronic schizophrenia, researchers reported here this week at the annual meeting of the American Psychiatric Association (APA). "The most important implication of this study is that it shows that aripiprazole is effective in significantly reducing the time-to-relapse as well as the rate of relapse in patients with schizophrenia who are being treated with medication," said lead investigator Teresa Pigott, MD, director of clinical trials in the department of psychiatry at the University of Florida School of Medicine in Gainesville, Florida. The purpose of the study was to assess the time to relapse with aripiprazole, compared to placebo, over 26 weeks in stable patients with chronic schizophrenia. The multicenter, randomized, double-blind, placebo-controlled study enrolled 310 subjects with chronic schizophrenia who were evaluated as stable, with no significant improvement or worsening in the previous three months and baseline on the Positive and Negative Symptoms for Schizophrenia (PANSS) scale of 82. They were randomized to aripiprazole 15 mg/day or placebo. Efficacy was determined by time to relapse, PANSS Total Score, and Clinical Global Improvement (CGI) score. Significantly fewer patients in the aripiprazole group (34 percent) relapsed by study end point compared to placebo (57 percent). Aripiprazole also increased the time to relapse by two fold. The agent was well tolerated , with an adverse events rate comparable to placebo, the researchers found. No significant changes occurred in Simpson-Angus Scale (SAS), Involuntary Movement Scale (AIMS), and Barnes Akathisia scores in either group. Weight gain in the aripiprazole group was comparable to placebo, Dr. Pigott said.

---------------------------------------------------------------------------------------------------------------------------------------

6]

Title: Meta-Analysis of the Efficacy of Aripiprazole in Schizophrenia: Presented at APA

By Bruce Sylvester PHILADELPHIA, PA -- May 23, 2002 –

Aripiprazole improves positive and negative symptoms of schizophrenia, with significant effects appearing one week after initiation of treatment. "The most important implication of this study is that aripiprazole 15 mg is shown to be effective in the treatment of schizophrenia. We also saw replicative efficacy in one or more studies in doses of 15 mg and above," said co-investigator William Carson, MD, group director in research and development at Bristol-Myers Squibb Research Institute in Wallingford, Connecticut. The presentation was made at the annual meeting of the American Psychiatric Association (APA). The meta-analysis included four- to six-week multicenter, double-blind, fixed-dose, placebo-controlled studies involving a total of 1,545 patients hospitalized with acute relapse of schizophrenia or schizoaffective disorder. The investigators randomized 898 subjects to aripiprazole, 381 to placebo, and the rest to active control: 167 to haloperidol 10 mg/day and 99 to risperidone 6 mg/day. Daily aripiprazole doses ranged from 2-30 mg. Weekly efficacy assessments included Positive and Negative Symptoms for Schizophrenia (PANSS) and Clinical Global Impression (CGI) scales. In the meta-analysis, aripiprazole showed superior efficacy to placebo at doses over 2 mg. The researchers also noted that aripiprazole dosing over 2 mg elicited significant improvement in PANSS-total score by week 1 (p<0.05). In examining the individual studies, the researchers found that aripiprazole dosing at 15 mg, 20 mg and 30 mg consistently produced significant improvements in PANSS-total score. They found similar PANSS-score changes from baseline for all aripiprazole groups. Across all of the studies, aripiprazole 15 mg, 20 mg and 30 mg produced significant improvements in other efficacy scores compared with placebo. In studies with active control, haloperidol and risperidone separated from placebo. "We had active comparator arms. Two of the active comparator drugs were haloperidol and risperidone. We saw efficacy that was comparable between aripiprazole and a typical antipsychotic, haloperidol, as well as an atypical antipsychotic, risperidone." Dr. Carson added. The study was supported by Bristol-Myers-Squibb.

---------------------------------------------------------------------------------------------------------------------------------------
7]

The Canadian Journal of Psychiatry (CJP) – February 2004
Aripirazole–Olanzapine Combination for Treatment of Schizophrenia

Dear Editor:

Recent literature is equivocal about antipsychotic combination in schizophrenia (1). However, the advent of the new antipsychotic aripiprazole, which has a mechanism of action different from other atypical antipsychotics, rekindles interest in this field. I describe a patient with schizophrenia showing partial response to olanzapine alone, but showing a marked improvement in symptoms (particularly the negative symptoms) on augmentation with aripiprazole. The possible mechanism of aripiprazole’s efficacy in negative symptoms is discussed.
Case Report
Mrs A, a 47-year-old woman with a long-standing history of schizophrenia, was admitted with a psychotic exacerbation precipitated by discontinuation of medicines. On mental status examination, she had marked psychomotor retardation, poverty of speech, flat affect, persecutory and referential delusions, loosening of association, and poor insight and judgment. She scored 122 on the Positive and Negative Symptom Scale (PANSS) with predominant negative symptoms (negative score 46, positive score 25). The patient was restarted on her previous antipsychotic; namely, olanzapine titrated to 20 mg daily, with further increase precluded by increased sedation. Despite 6 weeks on this dosage of olanzapine, there was modest improvement in positive symptoms but none at all in negative symptoms. In view of her partial response to olanzapine, aripiprazole was added at 15 mg daily as an augmenting agent. Within 2 weeks of this addition, the patient began to show improvement in her symptomatology. Her PANSS score dropped to 54 (a drop of 56%) after 6 weeks of olanzapine and aripiprazole combined. The positive, negative, and general psychopathology score decreased by 50%, 69%, and 45%, respectively. The patient was discharged on this combination and continues to maintain her improvement 2 months after discharge, at the same dosage of the 2 drugs. The notable improvement in negative symptoms deserves further attention; possible mechanisms are discussed below.
Olanzapine has a D2 receptor occupancy of 71% to 80% in the usual clinical dosage range of 10 to 20 mg daily, with the occupancy rising with dosage increase (2). Aripiprazole also shows a dose- dependent D2 receptor occupancy above 85% at dosages of 10 to 30 mg daily (3). With both olanzapine and aripiprazole having a high D2 receptor occupancy, one may question the rationale of combining these drugs. However, even at D2 occupancy values above 90%, extrapyramidal symptoms (EPS) are not observed with aripirazole (3). This may be attributed to aripiprazole’s being a partial agonist at the D2 autoreceptor. It would be interesting to explore how this mechanism may contribute toward improvement in negative symptoms.
Negative symptoms of schizophrenia have been hypothesized to result from a decrease in tonic dopamine transmission (4). Further, D2 autoreceptors tonically inhibit dopaminergic neurons (5). Stimulation of these receptors, as is the case with aripiprazole, induces their desensitization, leading to increased dopamine release (4). This novel mechanism may underlie aripiprazole’s low propensity to cause EPS and may also contribute toward its possible efficacy in negative symptoms. The previous generation of atypical antipsychotics, including clozapine, relies mainly on 5-HT2A antagonism for their greater efficacy in negative symptoms (6). Though aripiprazole also has a 5-HT2A antagonistic action, its role as a dopamine autoreceptor agonist may provide additional benefits for countering negative symptoms. Indeed, the study by Kane and colleagues showed that 15 mg daily, but not 30 mg daily, of aripiprazole produced a significantly greater improvement in PANSS negative subscale score, compared with placebo (7). There is some evidence to suggest that dopamine autoreceptor agonists do improve negative symptoms in schizophrenia patients with predominant negative symptoms (8). As aripiprazole acts as a dopamine agonist in the presence of significant receptor reserve for dopamine (which may be secondary to receptor upregulation following a hypodopaminergic state) (9), it can be speculated that schizophrenia patients with residual negative symptoms who are on potent D2 antagonists may benefit from the addition of small doses of aripiprazole. Further studies of aripiprazole at lower and higher dosages in primary negative symptoms are encouraged.
References
1. Freudenreich O, Goff DC. Antipsychotic combination in schizophrenia. A review of efficacy and risks of current combinations. Acta Psychiatr Scand 2002;106:323–30.
2. Kapur S, Zipursky RB, Remington G, Jones C, DaSilva J, Wilson AA, and others. 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry 1998;155:921–8.
3. Yokoi F, Grunder G, Biziere K, Stephane M, Dogan AS, Dannals RF, and others. Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C] raclopride. Neuropsychopharmacology 2002;27:248–59.
4. Moore H, West AR, Grace AA. The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia. Biol Psychiatry 1999;46:40–55.
5. Millan MJ, Gobert A, Newman-Tancredi A, Lejuene F, Cussac D, Rivet JM, and others. S33084, a novel, potent, selective, and competitive antagonist at dopamine D3-receptors: I. Receptor, electrophysiological and neurochemical profile compared with GR218,231 and L741,626. J Pharmacol Exp Ther 2000; 293:1048–62.
6. Meltzer HY. The role of serotonin in antipsychotic drug action. Neuropsychopharmacology 1999;21(Suppl 2):106S–15S.
7. Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito G, Zimbroff DL, and others. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002;63:763–71.
8. Wetzel H, Hillert A, Grunder G, Benkert O. Roxindole, a dopamine autoreceptor agonist, in the treatment of positive and negative schizophrenic symptoms. Am J Psychiatry 1994; 151:1499–2.
Harpreet S Duggal, MD, DPMPittsburgh,USA

---------------------------------------------------------------------------------------------------------------------------------------
8]

Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder
.Swainston Harrison T, Perry CM.Adis International Limited, Auckland, New Zealand.
Demail@adis.co.nz

Aripiprazole, a quinolinone derivative, is an atypical antipsychotic drug indicated for the treatment of adult patients with schizophrenia. Aripiprazole 10 or 15 mg once daily is effective and well tolerated in patients with schizophrenia or schizoaffective disorder. Although aripiprazole has only been directly compared with haloperidol and olanzapine in treatment-responsive patients to date, current data generally indicate that aripiprazole has a beneficial profile in terms of a low potential for bodyweight gain. Dosage titration is not necessary and the drug is effective in the first few weeks of treatment. Head-to-head comparative trials with atypical antipsychotic agents are required, as are long-term (> or =1 year) studies, to fully define the position of aripiprazole in relation to other antipsychotic drugs. Aripiprazole is a valuable new therapeutic option in the management of patients with schizophrenia.

Pharmacological properties:

Aripiprazole is a quinolinone derivative with a high affinity for dopamine D2 and D3 receptors, and serotonin 5-HT1A, 5-HT2A and 5-HT2B receptors. The mechanism of action of aripiprazole is not yet known, but evidence suggests that its efficacy in the treatment of the positive and negative symptoms of schizophrenia and its lower propensity for extrapyramidal symptoms (EPS) may be attributable to aripiprazole's partial agonist activity at dopamine D2 receptors. At serotonin 5-HT1A receptors, in vitro studies have shown that aripiprazole acts as a partial agonist whereas at serotonin 5-HT2A receptors aripiprazole is an antagonist. The main active metabolite, dehydro-aripiprazole, has affinity for dopamine D2 receptors and thus has some pharmacological activity similar to that of the parent compound. Aripiprazole is rapidly absorbed after oral administration. The mean time to peak plasma concentration is 3 hours following multiple-dose administration of aripiprazole 10 or 15 mg and the absolute oral bioavailability of the drug is 87%. Steady-state plasma drug concentrations are achieved by 14 days; however, the drug appears to accumulate over this period, since mean peak plasma concentration and mean area under the plasma concentration-time curve values of aripiprazole 10 or 15 mg/day are 4-fold greater on day 14 than on day 1. This accumulation may be expected, since the mean elimination half-life of a single dose of aripiprazole is about 75 hours. Aripiprazole has extensive extravascular distribution and more than 99% of aripiprazole and dehydro-aripiprazole (the main active metabolite of aripiprazole) is bound to plasma protein. Elimination of the drug is primarily hepatic; the cytochrome P450 (CYP) 3A4 and CYP2D6 enzyme systems transform aripiprazole to dehydro-aripiprazole, with the latter enzyme system subject to genetic polymorphism. Thus, dosage adjustment of aripiprazole is necessary when it is coadministered with CYP3A4 and CYP2D6 inhibitors (since aripiprazole concentration is increased) and with inducers of CYP3A4 (since aripiprazole concentration is decreased).

Therapeutic Efficacy:

The efficacy of aripiprazole has been demonstrated in patients with schizophrenia or schizoaffective disorder. In general, significant reductions from baseline in mean Positive and Negative Syndrome Scale total, positive and negative symptom scores, and Clinical Global Impression Severity of Illness scores were observed in patients with acute relapse of chronic schizophrenia or schizoaffective disorder receiving recommended (10 or 15 mg/day) or higher-than-recommended (20 or 30 mg/day) dosages of aripiprazole versus those receiving placebo in three well controlled, short-term trials. No additional therapeutic benefit was observed at the higher-than-recommended dosages. The drug is effective as early as the first or second week of treatment. The efficacy of aripiprazole was maintained for up to 52 weeks. The drug was significantly more effective than placebo in preventing relapse in patients with stable chronic schizophrenia in a 26-week, randomized trial. In a 52-week trial in patients with acute relapse of schizophrenia, the percentage of responders maintaining a response at study end was 77% of aripiprazole versus 73% of haloperidol recipients. Aripiprazole may improve cognitive function. In a nonblind, 26-week trial, patients with chronic schizophrenia receiving aripiprazole 30 mg/day experienced similar (general cognitive function) or better (verbal learning) changes from baseline in the neuro-cognitive parameters evaluated compared with recipients of olanzapine 10-15 mg/day.

Tolerability:

Aripiprazole 10-30 mg/day was generally well tolerated. The tolerability profile of aripiprazole was broadly similar to that observed with placebo in a meta-analysis of short-term trials in patients with acute relapse of schizophrenia or schizoaffective disorder and in a 26-week trial in patients with chronic stable schizophrenia. The most frequent treatment-emergent adverse events included insomnia and anxiety, and additionally, headache and agitation (in short-term trials) or akathisia and psychosis (in a 52-week trial). In general, the drug was associated with a placebo-level incidence of EPS and EPS-related adverse events. Significantly fewer aripiprazole recipients experienced EPS-related adverse events than haloperidol recipients in a 52-week trial. Changes in severity of EPS were minimal and usually no different from those observed with placebo. Moreover, there was less severe EPS in the aripiprazole group than the haloperidol group in a long-term trial. Treatment-emergent tardive dyskinesia was reported in only 0.2% of patients receiving aripiprazole (short-term trials), an incidence similar to that seen in placebo recipients (0.2%). Aripiprazole has a low propensity to cause clinically significant bodyweight gain, hyperprolactinaemia or corrected QT interval prolongation in patients with schizophrenia or schizoaffective disorder. In addition, there were no clinically relevant differences in mean changes from baseline in measures of diabetes and dyslipidaemia between the aripiprazole or placebo groups in a 26-week, placebo-controlled trial.

For further information, you can contact the following gentlemen:

Mr. Mukesh Vankani - General Manager (Cell# 09825032571) OR

Mr. Dipak Shah B.Pharm. MBA

at

reliancehealthcare@yahoo.co.in