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Comparison of Combination Olanzapine+Lithium or Chlorpromazine+Lithium in Treatment of First Manic Episode With Psychotic Features

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00202293
Recruitment Status : Completed
First Posted : September 20, 2005
Last Update Posted : August 31, 2018
Information provided by (Responsible Party):
Melbourne Health

Brief Summary:

Aim: In a population of first episode manic patients with psychotic features, we want to compare the side effect profile, the degree of adherence and the subjective well being, as well as the efficacy of two treatments: The standard treatment currently applied (lithium + chlorpromazine) and an alternative treatment more recently introduced (lithium + olanzapine). In addition, we want to study retrospectively the development of bipolar disorder and study prospectively the 6 and 12-month outcome of a cohort of patients presenting a first manic episode with psychotic features.

Research Background: While the efficacy of lithium in the treatment of acute mania has been established by numerous studies, it is also known that up to 50% of the patients fail to respond when it is prescribed alone. It is therefore common practice to complement the treatment, most commonly with antipsychotics and benzodiazepines. It has been suggested that antipsychotic agents are faster acting and are superior in controlling hyperactivity compared to lithium, whereas mood stabilisation is better achieved by lithium, Typical antipsychotics, such as chlorpromazine, may therefore be useful as adjunctive medication to mood stabilisers, especially within the first few weeks of treatment of acute mania, and for patients exhibiting psychotic symptoms or hyperactivity. They however can induce side effects (somnolence, dizziness, dry mouth, extrapyramidal side effects such as rigidity of the muscles, and possibly tardive dyskinesia (involuntary movements or contraction of muscles), as well as akathysia (sense of restlessness). They finally have been suspected to contribute to the occurrence of post-manic depression. Recent publications in chronic populations have shown that atypical antipsychotics, such as olanzapine, are also an effective adjunctive treatment. Olanzapine has the important advantage to induce a very low incidence of extrapyramidal side effects, including tardive dyskinesia. It can however induce somnolence, dizziness, dry mouth, and rather commonly weight gain. Moreover, some authors have reported that olanzapine might induce mania. Both treatments appear then to have positive effects as well as undesirable side effects. Our project is to compare them. The literature concerning first episode mania is sparse, particularly in the domain of pharmacotherapy. One retrospective study showed that 77% of the patients received antipsychotics at discharge and 25% at 6 months follow-up. No comparison has however been made between typical and atypical antipsychotics, and there are no specific treatment guidelines of first episode mania with psychotic features.

Project Summary: The hypothesis is that olanzapine and chlorpromazine will have a comparable efficacy as adjunctive treatment of the acute manic episode with psychotic features. We however think olanzapine will induce less side effects and will be better accepted by the patients, and therefore that the adherence to the treatment will be better than with chlorpromazine. We finally think the subjective sense of well being will be greater with olanzapine than with chlorpromazine.We will recruit 75 patients at the time of their first admission for mania with psychotic features at EPPIC. After signature of the informed consent, we will perform a baseline assessment first to confirm the diagnosis, and second to evaluate the level of psychopathology. The patients will then be randomly selected to receive either a treatment of lithium and olanzapine or a treatment of lithium and chlorpromazine. By the end of the study there will be 37 patients in each group.The patients will go through a baseline assessment including physical examination and usual laboratory investigation to exclude any physical illness. They will also go through a one-hour assessment of psychopathology. Between day 2 and 3 they will go through 2 hours of interview to reassess diagnosis and personal history. They will thereafter be assessed weekly for eight weeks on various dimensions: evolution of the intensity of the symptoms, appearance of depressive symptoms, occurrence of side effects and degree of adherence to the treatment, in an 1-hour interview. Subjective well being and quality of life will re evaluated at week 4 and 8, adding 45 minutes to the duration of the interview. This is a flexible dose, open trial, which means the doctor in charge of the patient will know which medication is being prescribed, and that he will be allowed to adapt the dosage according to what he feels necessary. This research project will allow us to organise a more specialised clinic for the care of first episode manic patients. We will take this opportunity to study carefully the months preceding the appearance of the first episode in order to try to reconstruct the prodrome of bipolar disorders. We will also, in an extension phase of the study, look at the long term outcome (at 6 and 12 months) of a first episode of mania.

Condition or disease Intervention/treatment Phase
Bipolar Disorder Schizoaffective Disorder Drug: Olanzapine Drug: Lithium Drug: Chlorpromazine Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 83 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single
Primary Purpose: Treatment
Official Title: Comparison of Combination Olanzapine and Lithium and Combination Chlorpromazine and Lithium in the Treatment of a First Manic Episode With Psychotic Features.
Study Start Date : October 1, 2001
Actual Primary Completion Date : November 1, 2015
Actual Study Completion Date : November 1, 2015

Arm Intervention/treatment
Experimental: Lithium and olanzapine Drug: Olanzapine
Drug: Lithium
Active Comparator: Lithium and chlorpormazine Drug: Lithium
Drug: Chlorpromazine

Primary Outcome Measures :
  1. Intensity of side effects [ Time Frame: 8 weeks ]
    Intensity of side effects

  2. ¨The frequency of treatment-emergent adverse events (events that first appear or worsen during the study period) will be compared between both groups. [ Time Frame: 8 weeks ]
  3. ¨The frequency of side effects as rated with the UKU scale will be compared between both groups. [ Time Frame: 8 weeks ]
  4. ¨Weight gain will be compared between both groups. [ Time Frame: 8 weeks ]
  5. ¨Frequency of changes in vital signs and laboratory findings will be compared between both groups. [ Time Frame: 8 weeks ]
  6. Subjective well being [ Time Frame: 8 weeks ]
  7. ¨Total scores on the DAI and the SWN will be compared between both groups. [ Time Frame: 8 weeks ]

Secondary Outcome Measures :
  1. Adherence [ Time Frame: 8 weeks ]
  2. ¨Degree of adherence to the treatment as scored on the MARS will be compared between both groups. [ Time Frame: 8 weeks ]
  3. Response to treatment [ Time Frame: 8 weeks ]
  4. ¨End point analysis: Mean change in various scales from baseline to week 4 and week 8 will be used to compare the efficacy of the two treatments: [ Time Frame: 8 weeks ]
  5. ¨Primary efficacy analysis will be assessed by comparing the mean change in theYMRS total score. [ Time Frame: 8 weeks ]
  6. ¨Secondary efficacy analysis will be assessed by comparing the mean change in CGI-BP total score and in BPRS total score. [ Time Frame: 8 weeks ]
  7. ¨Response analysis: Response is defined as at least a 50% drop in the total YMRS total score from base line to the 8-weeks end point. Euthymia is defined as a total score on the YMRS of no greater than 12 at end point. The number of patients reaching bot [ Time Frame: 8 weeks ]
  8. Incidence of depressive episodes [ Time Frame: 8 weeks ]
  9. ¨A worsening in the HAMD-21 score of at least 3 points will be used as a definition of a clinically detectable worsening in depressive symptoms. [ Time Frame: 8 weeks ]
  10. Six and 12 months outcome [ Time Frame: 12 months ]
  11. Definition of recovery: [ Time Frame: 12 months ]
  12. ¨Syndromic recovery: Eight contiguous weeks [50] during which the patient no longer meets criteria for a manic, mixed, or depressive syndrome. Recovery from each of these syndromes is based on DSM-IV criteria and is operationalised as follows: manic synd [ Time Frame: 12 months ]
  13. ¨Symptomatic recovery: Eight contiguous weeks [50] during which the patient experiences minimal to no psychiatric symptoms, operationalized as follows: Young Mania Rating Scale total score of 5 or less, Hamilton depression scale total score of 10 or les [ Time Frame: 12 months ]
  14. ¨Relapse: Relapse is defined as the return of symptoms after a remission of less than 8 weeks. [ Time Frame: 12 months ]
  15. ¨Recurrence: Recurrence is defined as return of symptoms after recovery. [ Time Frame: 12 months ]
  16. ¨Functional recovery: Return to premorbid levels of function for at least 8 contiguous weeks [50]. To assess functional recovery, seven of the nine general items from the Premorbid Adjustment Scale are evaluated at the 6 and 12-month follow-up visit for [ Time Frame: 12 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   15 Years to 29 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Male and female patients aged 15 to 29.
  • Experiencing a first episode psychosis.
  • Meet DSM-IV criteria for bipolar either manic or mixed episode, or schizoaffective disorder manic episode.
  • Minimum score of 20 on the YMRS
  • Written informed consent to participation.

Exclusion Criteria:

  • Patients at immediate risk of committing harm to self or others
  • Use of neuroleptics or mood-stabilisers in the two months preceding admission to EPPIC
  • Organic mental disease, including mental retardation
  • History of clinically significant illness (liver or renal insufficiency, significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurological or metabolic disturbances).
  • Clinically relevant biochemical or hematological abnormalities.
  • Pregnant or lactating woman
  • History of epilepsy
  • History of severe drug allergy or hypersensitivity
  • Non fluency in English.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00202293

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Australia, Victoria
ORYGEN Youth Health
Parkville, Victoria, Australia, 3052
Sponsors and Collaborators
Melbourne Health
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Principal Investigator: Philippe Conus ORYGEN Youth Health & Department of Psychiatry, The University of Lausanne
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Responsible Party: Melbourne Health Identifier: NCT00202293    
Other Study ID Numbers: 2001.013
First Posted: September 20, 2005    Key Record Dates
Last Update Posted: August 31, 2018
Last Verified: November 2015
Keywords provided by Melbourne Health:
Drug treatment
First episode
Additional relevant MeSH terms:
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Bipolar Disorder
Psychotic Disorders
Pathologic Processes
Bipolar and Related Disorders
Mental Disorders
Schizophrenia Spectrum and Other Psychotic Disorders
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Dopamine Antagonists
Dopamine Agents