Comparison of Combination Olanzapine+Lithium or Chlorpromazine+Lithium in Treatment of First Manic Episode With Psychotic Features
Condition: Bipolar Disorder; Schizoaffective Disorder
MeSH terms: Mania; Bipolar Disorder; Psychotic Disorders
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      This prospective single-centre open trial will compare two groups receiving two different
      neuroleptics combined with lithium during the first 8 weeks of treatment of a first manic
      episode. All the patients will also be included in a 6 and 12 months follow-up study and will
      provide information regarding the prodrome of bipolar illness.

      The trial comprises five phases: (1) Recruitment and screening; (2) Baseline assessment; (3)
      8 weeks treatment phase; (4) Follow-up.

        1. Recruitment and screening The Youth Access Team (YAT) assesses all the patients referred
           to the Early Psychosis Prevention and Intervention Centre (EPPIC) in order to confirm
           the diagnosis of first psychotic episode. Patients with a clinical presentation
           compatible with a diagnosis of first episode mania will be presented to the main
           investigator or to one of the co-investigators for a screening interview. This interview
           should take place as soon as possible, and not later than 24 hours after admission.
           During these 24 hours, the patients will be kept under a treatment of benzodiazepine
           exclusively.

           Any patient meeting the inclusion criteria (including a Young Mania Rating Scale (YMRS)
           [37] total scores equal or superior to 20) and none of the exclusion criteria at the
           screening interview will be informed (as well as his/her family) about the study, and
           they will receive a Patient Information Sheet. A Consent form will be completed if they
           agree to take part in the study. Patients under section 12 who are unable to give
           informed consent: these patients will be asked for consent when they are better. The
           authorised psychiatrist will be able to give consent to treatment on their behalf until
           they are well. When they are well and are asked to give consent and they do not give
           consent, all information gathered on this patient will be removed. If the patient
           declines to consent to the study, she/he will be offered standard clinical care in
           EPPIC.

        2. Baseline assessment Once informed consent will have been given, and provided the YMRS
           score 24 hours after admission remains greater than 20, patients will be assessed by a
           research assistant who will be blind to the treatment during the first 8 weeks of the
           study.

           ¨ The diagnosis will be based on clinical assessment according to the DSM-IV [38]
           criteria. It will be confirmed during the first week of the study by results of the
           Structured Clinical Interview for the DSM-IV, Patient Version (SCID-P) [38].

           ¨ The severity of the illness will be evaluated at baseline with the YMRS, the BPRS, the
           Clinical Global Impression bipolar version (CGI-BP) [39] and the Global Assessment of
           Functioning (GAF) [38].

           ¨ The depressive symptoms will be assessed with the 21-item Hamilton Depression Rating
           Scale (HAMD-21) [40].

             -  Substance abuse comorbidity will be assessed during the first week with the PACE
                Substance Use Questionnaire (PSUQ)

             -  Level of functioning will be assessed with the Quality if Life Scale (QLS) [41],
                the Premorbid Adjustment Scale (PAS) [42] and the Modified Vocational Status Index
                (MVSI) and the Modified Location Code Index (MLCI) [43] during the first week of
                treatment. If necessary the participation of relatives will be asked.

           In addition, the subjects will undergo physical examination, including blood test, for
           safety reasons. Demographic data, vital signs, and details on any concomitant medication
           and medical history will also be collected.

           ¨ Laboratory tests: Haematology: Haemoglobin, MCH, MCHC, MCV, RBC, WCC, platelets,
           haematocrit. Biochemistry: Total bilirubin, total protein albumin, AST, ALT, alkaline
           phosphatase, urea, creatinine, sodium, potassium, prolactin, cholesterol, triglycerides,
           glucose, thyroid function tests (freeT4 and TSH), prolactine level.

        3. 8-week Treatment phase: The Australian Clinical Guidelines for Early Psychosis [44]
           suggest that first episode patients should ideally be observed during 24 hours before
           any medication is started. This rule will also be applied in the context of the study.
           During this period, the medication will be restricted to benzodiazepines except in case
           of severe agitation. In case of severe agitation neuroleptics will be prescribed, if
           possible after informed consent and randomisation.

           Patients will thereafter be randomly assigned to one of two groups: olanzapine +
           lithium, or chlorpromazine + lithium. The raters (research assistant and one
           psychiatrist in charge of the rating of the side effects) will be blind to the
           randomisation process and treatment conditions during the first 8 weeks of the trial.

           Each subject will also be allocated to a case manager and a psychiatrist who will be one
           of the investigators. The psychiatrist in charge of the patient will not be blind to the
           treatment, and therefore will not do the rating of side effects. A research assistant
           will conduct all the psychometric assessments across the 12 months of the study and will
           remain blind to the medication received during the first 8 weeks of the trial. During
           this eight weeks period, patients will be seen according to clinical needs, and will be
           met weekly up to week 4 and then on week 6 and 8 for assessment of current levels of
           psychopathology, the collection of safety data and assessment of compliance. After the
           first 8 weeks of treatment, the psychiatrist will be free to change the treatment.
           Neurolpetics will be continued for a minimum of 6 months and lithium for a minimum of 12
           months. Lithium serum level will be assessed at day 4 and 7, and then accordingly to the
           stability of the blood level.

        4. Follow-up prospective evaluation:

           In this phase, the aim is to compare the level of side effects under each medication
           regimen, the subjective well-being and the adherence to the treatment during the first 8
           weeks on treatment. Other aims are to assess the efficacy of both treatments, the
           incidence of depressive symptoms, and the 6 and 12 months outcome.

           ¨ Side-effects will be assessed weekly with the UKU rating scale.

             -  Adherence to the medication will be assessed weekly with the Medication Adherence
                Rating Scale (MARS).

             -  Subjective well-being will be assessed with the Drug Attitude Inventory (DAI) and
                the Subjective Well-Being Under Neuroleptics Scale (SWN) at week 1,4 and 8.

             -  The severity of the illness will be prospectively evaluated on a weekly basis until
                week 4, and then at week 6 and 8, month 6 and month 12 with the YMRS, the BPRS and
                the CGI-BP.

             -  Depressive symptoms will be assessed at the same time lines with the HAMD-21.

             -  Substance abuse comorbidity will be reassessed at week 8, month 6 and month 12 with
                the PSUQ.

             -  Change inn the level of functioning will be assessed with the QLS, the PAS and the
                MVSI and MLCI at month 6 and month 12.

             -  Vital signs and weight change will be reassessed at weeks 4 and 8 and at months 6
                and 12, or whenever necessary.

             -  Laboratory values will be reassessed at week 8, or whenever necessary.

           SUBJECTS TRIAL SAMPLE The aim is to recruit 75 first episode manic patients over a two
           years period. EPPIC takes care of 60 to 80 first episode manic patients each year and we
           plan on a recruitment rate of 50%.

           TREATMENT Trial drugs

           Lithium: Lithium will be started at 500mg per day on day one and will be increased to
           500 mg bd from day 2. Serum lithium will be assessed on day 4, and the daily dose of
           lithium will be adapted accordingly. Serum lithium will be assessed again on day 7 and
           thereafter once or twice a week depending on the previous results. We will aim at
           keeping the lithium level between 0.5 and 1.0 mEq/l, ideally between 0.8 and 1.0 mEq/l.
           (Higher levels are not recommended when lithium is prescribed along with antipsychotics
           [49] Chlorpromazine: Chlorpromazine will be started at 100 mg/day orally and adjusted
           from day 2 by steps of 50 mg or 100 mg, upwards or downwards. Chlorpromazine will be
           continued for a minimum of 6 months, and will be interrupted according to the clinical
           state.

           Olanzapine: Olanzapine will be started at 5mg/day and adjusted by steps of 2.5mg each
           day according to the clinical picture, upwards or downwards. Olanzapine will be
           continued for a minimum of 6 months, and will be interrupted according to the clinical
           state.

           CONCOMITANT MEDICATION All medications (prescribed or over-the-counter medications) that
           are ongoing at the start of the trial or started during the trial, must be documented in
           the file.

           The following medications are allowed, under specified circumstances:

           Diazepam: up to 50 mg/day to alleviate severe agitation. Benztropine: up to 4 mg/day,
           for treatment-emergent extrapyramidal symptoms. Paroxetin: will be prescribed in case of
           the occurrence of a depressive episode that persists after optimisation of the lithium
           treatment and interruption of antipsychotics.

           ASSESSMENTS Safety ¨ The frequency of treatment-emergent adverse events (events that
           first appear or worsen during the study period) will be compared between both groups.

           ¨ The frequency of side effects as rated with the UKU scale will be compared between
           both groups.

           ¨ Weight gain will be compared between both groups.

           ¨ Frequency of changes in vital signs and laboratory findings will be compared between
           both groups.

           Subjective well- being

           ¨ Total scores on the DAI and the SWN will be compared between both groups.

           ASSESSMENT OF SECONDARY OBJECTIVES Adherence

           ¨ Degree of adherence to the treatment as scored on the MARS will be compared between
           both groups.

           Efficacy

           ¨ 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:

           ¨ Primary efficacy analysis will be assessed by comparing the mean change in theYMRS
           total score.

           ¨ Secondary efficacy analysis will be assessed by comparing the mean change in CGI-BP
           total score and in BPRS total score.

           ¨ 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 both of
           these levels of improvement in both groups will be compared.

           Incidence of depressive episodes ¨ 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.

           Six and 12 months outcome

           Definition of recovery:

             -  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 syndrome-no longer meeting the A or B criterion for a manic episode;
                depressive syndrome-no longer meeting the A criterion for a major depressive
                episode; mixed syndrome-no longer meeting the A or B criterion for a manic episode
                and the A criterion for a major depressive episode.

             -  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 less.

             -  Relapse: Relapse is defined as the return of symptoms after a remission of less
                than 8 weeks.

             -  Recurrence: Recurrence is defined as return of symptoms after recovery.

             -  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 the interval period (excluding ratings of education and
                abruptness in the change in work associated with the index episode, since these
                scores can not change). To meet criteria for functional recovery, subjects has to
                receive Premorbid Adjustment Scale general item interval scores less than or equal
                to the premorbid rating on five of the seven items and have no interval item score
                more than 2 points higher than the corresponding premorbid score. Additionally,
                functional recovery will be considered to be realised if patients return to at
                least base level on both MLCI and MVSI.
    

Intervention name(s): Olanzapine; Lithium; Chlorpromazine
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Olanzapine; Chlorpromazine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single
Primary purpose: Treatment
Keywords: Bipolar; Mania; Drug treatment; First episode; Psychosis; Therapy; Antipsychotic