To examine the effect of L-dopa addition to optimal D2-blocking antipsychotic treatment on positive symptoms, negative symptoms, cognitive symptoms and extrapyramidal symptoms in schizophrenia.
ID
Source
Brief title
Condition
- Schizophrenia and other psychotic disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- change in verbal learning as assessed by the Hopkins Verbal Learning Test
Revised (HVLT-R), as compared between patients receiving L-dopa vs those
receiving placebo
- change in working memory as assessed by the N-back task, as compared between
patients receiving L-dopa vs those receiving placebo
- change in the severity of negative symptoms, as assessed by the PANSS
negative symptoms subscale, as compared between patients receiving L-dopa vs
those receiving placebo
Secondary outcome
- change in the severity of positive symptoms, as assessed by the PANSS
positive symptoms subscale, as compared between patients receiving L-dopa vs
those receiving placebo
- change in cognitive functions other than working memory and verbal memory, as
tested by the MATRICS, as compared between patients receiving L-dopa vs those
receiving placebo
- change in frontal functions as assessed by the FAB (Frontal Assessment
Battery), as compared between patients receiving L-dopa vs those receiving
placebo
- change in extrapyramidal symptoms, as scored by the ESRS, as compared between
patients receiving L-dopa vs those receiving placebo
- change in general functioning as scored by the HoNOS (Health of the Nations
Outcome Scale) and CGI (Clinical Global Impression - severity scale), as
compared between patients receiving L-dopa vs those receiving placebo
- change in subjective well-being, as assessed by the SWN (Subjective
Well-being under Neuroleptics), as compared between patients receiving L-dopa
vs those receiving placebo
Background summary
Schizophrenia is the psychiatric disorder with the worst prognosis. Its
lifetime prevalence is about 1%, the disorder starts at an early age and has a
chronic course. The symptoms of schizophrenia can be divided into positive
symptoms (hallucinations, delusion, formal thought disorder, catatonic
symptoms), negative symptoms (affect flattening, loss of interest, social
withdrawal) and decline in cognitive functions. Although the exact
neurobiological substrates for schizophrenia remain unclear, it is widely
accepted that a disbalance in dopaminergic neurotransmission plays a key role
in psychosis. The classic dopamine (DA) hypothesis proposes that increased
striatal DA transmission mediates positive psychotic symptoms in schizophrenia.
While positive symptoms generally respond rather well to antipsychotic
treatment, negative symptoms are only minimally affected or even exacerbated.
Hence, even patients with schizophrenia in which antipsychotic (D2-blocking)
treatment has been optimized, often suffer from debilitating long-term negative
symptoms, leading to a serious decline in quality of life. Another point of
interest is the fact that antidopaminergic antipsychotic treatment can have
extrapyramidal side effects, such as acute dystonia (sustained, often painful
muscular spasms, producing twisting abnormal postures), parkinsonism, akathisia
(feeling of inner restlessness and a compelling need to be in constant motion)
and in the long term irreversible tardive dyskinesia (involuntary, repetitive
movements), which have been reported to ameliorate after addition of L-dopa.
In contrast to positive psychotic symptoms, cognitive dysfunction and negative
psychotic symptoms have been related to a reduction of DA activity in other
areas of the brain, especially the prefrontal cortex (PFC). Increase of
cortical DA type 1 (D1) receptor activity has been proposed to correlate with
amelioration of cognitive dysfunction and negative symptoms in schizophrenia.
Until now, no selective D1 agonists are available for human use. Attempts to
activate cortical dopamine transmission by adding L-dopa to conventional
(D2-blocking) antipsychotic treatment have reported promising results. However,
these studies show several inconsistencies, which can largely be attributed to
methodological differences, small sample size, and flawed study design.
Study objective
To examine the effect of L-dopa addition to optimal D2-blocking antipsychotic
treatment on positive symptoms, negative symptoms, cognitive symptoms and
extrapyramidal symptoms in schizophrenia.
Study design
double-blind, randomized, placebo-controlled
Intervention
25 patients receive Sinemet in a build-up dosing schedule:
days 1-4: 4 dd 50 mg
days 5-8: 2 dd 100 mg, 2 dd 50 mg
days 9-12: 4 dd 100 mg
days 13-16: 2 dd 150 mg, 2 dd 100 mg
days 17-20: 4 dd 150 mg
days 21-24: 2 dd 200 mg, 2 dd 150 mg
days 25-42: 4 dd 200 mg
25 patients receive a placebo
Study burden and risks
The burden for participants is small. The side effects of Sinemet (involuntary
movements, sleepiness, dizziness, mood changes, raised blood pressure and
nausea, (re)occurrence or worsening of positive psychotic symptoms) are
generally mild and the change of the occurrence of side effects is further
decreased by simultaneous use of haloperidol or risperidone.
Substantial parts of the examinations (PANSS) are routine diagnostics and are
standard procedure for patients admitted to the psychosis ward of the Erasmus
MC. The other examinations will ask time from the participants, but are not
invasive or tiring.
There are no risks associated with the tests and questionnaires used.
's Gravendijkwal 230
3015 CE Rotterdam
NL
's Gravendijkwal 230
3015 CE Rotterdam
NL
Listed location countries
Age
Inclusion criteria
All patients will be recruited from the Psychiatry ward of the Erasmus Medical Center, Rotterdam, and diagnosed according to DSM-IV criteria by a senior psychiatrist Patients will be included if they meet the criteria for schizophrenia. Further inclusion criteria inpatients aged 18-40 years with a diagnosis of schizophrenia, stable under haloperidol or risperidone treatment (<=20 points, or >3 points on no more than three items on PANSS positive symptom scale), with significant negative symptoms (total of >20 points, or >3 points on two items on PANSS negative symptom scale) are eligible for the study.
Exclusion criteria
pregnancy,use of psychotropic medication other than benzodiazepines serious neurological disorders. Subjects will also be excluded when they cannot understand Dutch language sufficiently to understand the purposes and implications of the experiment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-019897-33-NL |
| CCMO | NL32185.078.10 |