Safety and Efficacy of Aripiprazole and Ziprasidone Among Schizophrenic Patients With Metabolic Syndrome
Condition: Schizophrenia
MeSH terms: Metabolic Syndrome; Schizophrenia
Study type: Interventional
Phase: Phase 4

Summary: 
      Introduction:

      Schizophrenia is a serious mental illness. For majority of patients it is a lifetime
      condition,characterized by intermittent episodes of hospitalization due to relapse or acute
      symptom exacerbation. The nature and course of the disorder impose significant social and
      economic burden. Relapse is costly, with hospitalization accounting for a substantial portion
      of healthcare expenses. Second generation antipsychotic side effect such as metabolic
      syndrome and diabetes mellitus will contribute additional costs to the treatment.

      Many studies have since then provided convincing evidence for a high risk of diabetes and
      other glucose abnormalities, metabolic syndrome and mortality due to elevated cardiovascular
      risk in patients with schizophrenia.

      However many studies has shown the effectiveness and safety of aripiprazole and
      ziprazidone.In one of the study, aripiprazole showed improvement of negative schizophrenic
      symptoms by 25% and 50% of functioning level from baseline. In term of safety, antipsychotics
      considered to have a safer metabolic profile were amisulpride, ziprasidone and aripiprazole.

      Study objectives:

        -  To investigate the safety and efficacy of ziprazidone versus aripiprazole in the
           treatment of schizophrenia patients with metabolic syndrome and diabetes mellitus.

        -  To investigate the reversibility of metabolic syndrome and diabetes parameters following
           the treatment with ziprazidone versus aripiprazole.

      Hypotheses:

      * The proportion of reversibility of metabolic syndrome and diabetes parameters is higher
      following the treatment of ziprazidone than aripiprazole.
    

Detailed description: 
      Introduction:

      Schizophrenia is a devastating mental illness that impairs mental and social functioning and
      often leads to the development of comorbid diseases. Metabolic abnormalities have
      historically been associated with illness such as schizophrenia. Many studies have since then
      provided convincing evidence for a high risk of diabetes and other glucose abnormalities,
      metabolic syndrome and mortality due to elevated cardiovascular risk in patients with
      schizophrenia. These metabolic abnormalities are of major clinical concern not only because
      of their direct somatic effects on morbidity and mortality but also because of their
      association with psychiatric outcome, such as a higher prevalence of psychotic and depressive
      symptoms, a lower functional outcome, a worse perceived physical health, and lower adherence
      to medication.

      Effective pharmacologic treatment of schizophrenia has been available since the 1950s. The
      first-generation antipsychotics had an increased risk of extrapyramidal side effects, such as
      dystonic reactions (example, fixed upper gaze, neck twisting, facial muscle spasms),
      parkinsonian symptoms (example, rigidity, bradykinesia, shuffling gait, tremor), and
      akathisia (example, inability to sit still, restlessness, tapping of feet).

      The term "atypical antipsychotic" refers to newer antipsychotics that confer less risk of
      extrapyramidal side effects than traditional antipsychotics. Although newer atypical
      antipsychotics are associated with fewer neurologic side effects, they had a higher risk of
      metabolic side effects such as diabetes, hypercholesterolemia, and weight gain. This effect
      is independent from the development of diabetes; the exact mechanism by which atypical agents
      might cause diabetes is unknown. Few drugs such as aripiprazole, sertindole, amisulpride and
      ziprasidone were found to have promising effect in lowering metabolic syndrome.

      The study is designed to:

        1. Identify safer treatment and high efficacy in schizophrenia. The efficacy of ziprasidone
           in the treatment of schizophrenia has been demonstrated in both short-term and long-term
           controlled trials. Ziprasidone has been shown to be comparable to haloperidol,
           olanzapine and risperidone in alleviating overall psychopathology, improving associated
           depressive symptoms and cognitive function in schizophrenia. Ziprasidone was generally
           well tolerated in these trials, with a weight-neutral profile, with limited
           discontinuations related to adverse events.

           Ziprasidone has exhibited a low incidence of weight gain, and one analysis suggested it
           carries a lower liability for weight gain than other atypical agents. In an open-label
           study, patients whose medication was switched to ziprasidone from conventional
           antipsychotics, risperidone, or olanzapine exhibited improvement in the lipid profile.
           Ziprasidone has also demonstrated a low incidence of extrapyramidal symptoms and a low
           risk of prolactin elevation. It has been associated with modest prolongation (<10
           milliseconds) of the corrected QT(QTc) interval on electrocardiography(ECGs) obtained
           during short-term, fixed-dose, placebo-controlled trials evaluating doses of up to 200
           mg/day. A study evaluating QTc intervals at maximum steady-state plasma concentrations
           demonstrated a 9-14-msec greater increase in QTc interval with ziprasidone than with
           four other atypical antipsychotics, including olanzapine . The clinical relevance of
           this magnitude of change is unclear. No excess risk of cardiac sequelae was observed in
           the clinical development program (package insert for Geodon [ziprasidone], Pfizer Inc.,
           New York, 2002).

           Published data regarding the efficacy of aripiprazole in the treatment of schizophrenia
           indicate superiority to placebo and comparability to risperidone, in Positive and
           Negative Syndrome Scale (PANSS) total and Clinical Global Impression of Severity (CGI-S)
           improvement scores. In these studies, aripiprazole demonstrated a favourable safety and
           tolerability profile, with little propensity for weight gain or other adverse metabolic
           effects.

        2. Improving clinical practice This study will provide findings for the clinician to be
           used later in the management of schizophrenia especially prognosis of the patient. The
           aim is to achieve good outcome and minimising the side effects especially those causing
           development of comorbidity.

      Second-generation (atypical) antipsychotics have become first-line medications for the
      treatment of schizophrenia and schizoaffective disorder, in large part due to their
      consistently reduced association with movement disorders and comparable efficacy to
      conventional agents. Direct comparisons among the atypical agents are, however, limited. In
      contrast to earlier atypical antipsychotic agents, ziprasidone and aripiprazole share a
      reduced propensity for weight gain and metabolic dysregulation. Given that obesity and
      dyslipidemia are highly prevalent and probable contributors to the elevated rates of
      morbidity and premature mortality among individuals with schizophrenia, these newer atypical
      agents offer the potential for improved health outcomes in this population.

      Obesity is a threat to health and longevity. Given that over one-third of the adults in the
      United States are obese, practices causing major weight gain deserve careful consideration.
      Obesity and weight gain have been associated with hypertension, type II diabetes, coronary
      heart disease, stroke, gallbladder disease, osteoarthritis, sleep apnoea and respiratory
      problems, and some types of cancer (endometrial, breast, prostate, and colon). Moreover,
      obesity is a common concomitant of schizophrenia, and schizophrenic individuals appear to be
      at increased risk for certain obesity-related conditions such as type II diabetes and
      cardiovascular disease.

      Weight gain may also cause patients taking antipsychotic medications to discontinue their
      medications, which may predispose them to relapse. Historically, the extrapyramidal side
      effects of antipsychotics outweighed any non-extrapyramidal side effects. With the advent of
      newer "atypical" antipsychotics, extrapyramidal side effects are becoming less of a problem.
      For other drugs, the degree of weight gain, estimated by the random effects regression at 10
      weeks, ranged from 0.04 kg for ziprasidone (not significantly different from zero) to 4.45 kg
      for clozapine. Among the five new atypical antipsychotics in the study (ziprasidone,
      risperidone, sertindole, olanzapine, and clozapine), ziprasidone had the lowest weight gain
      (0.04 kg) and clozapine had the highest (4.45 kg).

      This study will determine whether antipsychotic-associated metabolic syndrome and diabetes
      mellitus can be reversed by switching to aripiprazole and ziprazidone. Currently there is no
      data available on the above issue.
    

Intervention name(s): Ziprasidone; Aripiprazole
Intervention type(s): Drug; Drug
Intervention description(s): Ziprasidone's activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of ziprasidone are dose-proportional within the proposed clinical dose range, and ziprasidone accumulation is predictable with multiple dosing. Elimination of ziprasidone is mainly via hepatic metabolism with a mean terminal half-life of about 7 hours within the proposed clinical dose range.
Steady-state concentrations are achieved within one to three days of dosing. The mean apparent systemic clearance is 7.5 mL/min/kg. Ziprasidone is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes. Ziprasidone is well absorbed after oral administration, reaching peak plasma concentrations in 6 to 8 hours.; Aripiprazole activity is presumably primarily due to the parent drug, aripiprazole and to a lesser extent, to its major metabolite, dehyrdro-aripiprazole. Steady state concentrations are attained with in 14 days of dosing. The mean elimination half lives are about 75 hours and 95 hours respectively. Elimination of aripiprazole is mainly through hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4. Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3-5 hours; the absolute oral bioavailability of the tablet formulation is 87%. Absorption of aripiprazole is not affected by food.
Other intervention name(s): Zeldox; Abilify
Intervention MeSH terms: Aripiprazole; Ziprasidone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Randomized; Controlled; Trial; Safety; Efficacy; Aripiprazole; Ziprasidone; Metabolic Syndrome