Trial document




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  DRKS00006854

Trial Description

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Title

Study on promotion of appetite after olanzapine in healthy volunteers

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Trial Acronym

Olanzapine and appetite

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URL of the Trial

[---]*

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Brief Summary in Lay Language

Olanzapine is a marketed drug since many years. It is used to treat psychiatric disorders particularly schizophrenia, mania, depression and obsessive compulsive disorder. Olanzapine is a so-called atypical antipsychotic. These drugs mean a distinct progress in treatment of the mentioned disorders since they induce less side effects and are more effective than older drugs in the same field. However increased appetite with consequent weight gain is a frequent side effect of olanzapine and some other atypical antipsychotics. After longer treatment the weight gain increases the risk of somatic diseases like hypertension and diabetes type II. In order to help the psychiatric patients who are treated with olanzapine and similar drugs, it is an urgent need to understand how these drugs induce increased appetite. A better knowledge how this side effect develops helps to avoid it. The aim of this study is to understand better, how increased appetite after olanzapine develops. We want to examine in this clinical tria in healthy volunteers l whether after intake of olanzapine the secretion of certain hormones, the so-called neuropeptides changes after showing of pictures and whether certain processes during sleep which are related to appetite are changed in comparison to the interval before the intake of the drug.

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Brief Summary in Scientific Language

A frequent side effect of several atypical antipsychotics which are prescribed to many patients is an increase of appetite resulting in weight gain and an elevated risk of somatic disorders, particularly hypertension, hyperlipidemia, coronary heart disease and type II diabetes (Pascot et al., 2000). This adverse increase of appetite and its consequences occur also after olanzapine (Kinon et al., 2001). The mechanisms of this increase of appetite are still widely unknown.
The most distinct known endogenous stimulus for appetite and weight gain in humans is the neuropeptide ghrelin. Ghrelin was identified by Kojima et al. (1999) in the stomach, the brain and other tissues of humans and rats. Ghrelin is an endogenous ligand of the growth hormone-secretagogue receptor. After exogenous ghrelin food intake is elevated in rats (Tschöp et al., 2000; Wren et al., 2000). Also in healthy human subjects after ghrelin administration increase of appetite and elevated calory intake were found (Wren et al., 2001). Our research group observed, that nocturnal administrations of 4 x 50 µg ghrelin promote sleep, whereas one injection of 100 µg induced distinct hunger and elevated food intake (Weikel et al., 2003). Furthermore we showed that presentation of pictures showing food prompted an increase of ghrelin levels in healthy volunteers in contrast to the presentation of neutral pictures (Schüssler et al., 2012).
It is unknown, whether this effect is influenced by olanzapine. Controversial reports exist on the effect of olanzapine on the levels of ghrelin and other endogenous substances involved in metabolism like insulin and the appetite-inhibiting peptide leptin and peptide YY (PYY). Murashita et al. (2005) found increases of body weight and ghrelin after treatment with olanzapine in schizophrenic patients. In contrast Hosojima et al. (2006) reported, that in another study in patients with schizophrenia after olanzapine body weight and leptin increased, insulin remained unchanged and ghrelin levels decreased. In animal model olanzapine induced in rats weight gain, increase of ghrelin and decrease of insulin, whereas PYY remained unchanged (Weston-Green et al., 2011). Zhang et al. (2013) suggested a triphasic effect of olanzapine. According to these authors olanzapine first induced an elevation of ghrelin levels which was followed by decrease due to feedback inhibition related to weight gain. Later on ghrelin increased again.
Another new approach to investigate the influence of eating by drugs is the use of standardized low resolution brain electromagnetic tomography (sLORETA) related to sleep-EEG recording. sLORETA is a functional brain imaging method. Similar to functional magnetic resonance imaging (fMRI) the aim of sLORETA is imaging of brain activity. In contrast to fMRI which is related with high noise and unconvenient position in the tomograph and therefore makes sleeping difficult, sLORETA is based on nocturnal recordings in the sleep laboratory with a special cap with 118 EEG electrodes. This approach does not prompt relevant impairment of sleep. sLORETA allows to localize under ideal conditions the course of electrical signals in the three dimensional cortex exactly by 100%. No other linear tomography method matches with this capacity of sLORETA. By sLORETA the area of localization is reduced from 2-3 voxel to 0 (Pascual-Marqui et al., 2002). It is possible to examine deep regions of the brain as the region of the subgenual anterior singular cortex (sgACC). This sgACC brain region has distinct anatomic connections to other special brain regions as amygdala, hippocampus and hypothalamus (Chiba et al., 2001; Johansen-Berg et al., 2008). Therefore a role in the regulation of mood, sleep, libido and particularly appetite is likely (Pizzagalli, 2011). So far an examination of the sgACC brain region after olanzapine is lacking. It is likely, that sgACC activity increases after olanzapine. The brain area sgACC, amygdala, hippocampus and hypothalamus are parts of the prae-/limbic system. This system is more active during REM sleep than during wakefulness. At the same time brain structures in its neighborhood at the prefrontal cortex are deactivated (Braun et al., 1997), probably resulting in a higher signal -2-noise-ratio, with ”signal” meaning the relevant sgACC activity and “noise” meaning unspecific basic activity. REM sleep appears to be more appropriate for recordings related to the aim of the study than wakefulness. We expect that by this approach the effect of olanzapine in comparison to baseline can be better delineated. Probably sgACC activity increases after olanzapine.
The aim of this study is to clarify whether treatment with olanzapine for seven days in healthy volunteers (i) influences the effect of pictures showing food on the secretion of ghrelin and plasma levels of other endogenous substances involved in metabolism as leptin, insulin and PYY, (ii) influences their basal plasma concentrations and (iii) whether the activity of an appetite-regulating brain region, investigated by sLORETA is influenced by this medication. A better understanding of the mechanisms of increased appetite after olanzapine would help to prevent this important unwanted effect.

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Organizational Data

  •   DRKS00006854
  •   2014/11/14
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  •   yes
  •   Approved
  •   320-14 fed, Ethik-Kommission der Medizinischen Fakultät der Ludwig-Maximilians-Universität München
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Secondary IDs

  •   2014-002682-30 
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Health Condition or Problem studied

  •   healthy volunteers
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Interventions/Observational Groups

  •   The subjects receive during seven days at 20:00 Olanzapin (Zyprexa ®) orally as a pill. Tehe dosages are
    at Days 1 and 2: 2.5 mg,
    at Days 3 and 4: 5.0 mg,
    at Days 5 bto 7: 10,0 mg.
    If a subject does not tolerate the dose of 10 mg
    it will be reduced to 5 mg.
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Characteristics

  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Basic research/physiological study
  •   Single (group)
  •   IV
  •   No
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Primary Outcome

The main objective of the trial is to investigate, whether in healthy
subjects the effect of pictures showing food on ghrelin plasma concentrations is more distinct after seven
days of treatment with olanzapine than at baseline, before treatment.

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Secondary Outcome

Secondary objectives are to investigate wheter in healthy subjects
(i)the activity in the brain area subgenuale anterior cingulate cortex
(sgACC), measured during REM sleep by sLORETA differs after 7 days of
treatment with olanzpine from baseline conditions,
(ii)ghrelin plasma concentrations after showing neutral pictures differ from those after
showing pictures with food at baseline and after olanzapine as well,
(iii)plasma concentrations between 08:00 and 13:00 of ghrelin, leptin,
insulin, PYY and other substance invoved in metabolism differ between
baseline and 7 days of treatment with olanzapine
(iv)self rated appetite differs between baseline and 7 days of treatment
with olanzapine.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • Medical Center 
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Recruitment

  •   Actual
  •   2014/10/15
  •   10
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Male
  •   18   Years
  •   30   Years
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Additional Inclusion Criteria

Healthy male volunteers. During the last 6 months
they should have regularly three meals per day.

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Exclusion Criteria

• acute physical and psychiatric disorders
•psychiatric disorders in the own and family history
•any drug treatment exceeding two days during the last three months
and exceeding one day during the last month
•participation in another clincal trial at the same time or during the last
four weeks
•smoking
•monodirectional diets like vegetarian during the last six months
• chanfges of body weight, more than 2 kg during the last year
• high performance sport
•seriously defective vision
•intolerance to olanzapine or additives

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Addresses

  • start of 1:1-Block address primary-sponsor
    • Max-Planck-Institut für Psychiatrie
    • Mr.  Prof. Dr.  Axel  Steiger 
    • Kraepelinstr. 2-10
    • 80804  München
    • Germany
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    • Max-Planck-Institut für Psychiatrie
    • Mr.  Prof. Dr.   Axel  Steiger 
    • Kraepelinstr. 2-10
    • 80804  München
    • Germany
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    • Max-Planck-Institut für Psychiatrie
    • Mr.  Prof. Dr.  Axel  Steiger 
    • Kraepelinstr. 2 -10
    • 80804  München
    • Germany
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Sources of Monetary or Material Support

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    • Max-Planck-Institut für Psychiatrie
    • Mr.  Prof. Dr.   Axel  Steiger 
    • Kraepelinstr. 2-10
    • 80804  München
    • Germany
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Status

  •   Recruiting complete, follow-up complete
  •   2016/05/19
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.