Clonidine Augmentation Treatment in Schizophrenia

Schizophrenia is a major debilitating mental disease with an incidence of
approximately 1% in the general population worldwide. Currently available
antipsychotics are only effective in reducing positive symptoms, without
restoring cognition or alleviating negative symptoms. Between one-fifth and
one-third of patients have little, if any, benefit from them. Treatment of
these patients remains a persistent public health problem, as treatment
resistant patients are often highly symptomatic, have a severely reduced
quality of life and need extensive periods of hospital care. Therapy-resistant
Schizophrenia patients also require a disproportionately high amount of the
total health costs for schizophrenia. Clonidine is a noradrenergic *2A agonist,
usually prescribed in the treatment of hypertension, but also in the treatment
of Tourette*s syndrome and in the treatment of children with ADHD. Results of a
recent performed pilot study from our study group and literature point at a
potentially positive effect of clonidine on certain aspects of schizophrenia.
In our pilot study we found that in schizophrenia patients very often disturbed
parameters of basic information processing normalized when they were treated
with only one administration of low dose (between 25 and 75 µg) of clonidine.
In schizophrenia, there is a correlation between these parameters of basic
information processing and cognitive functioning, symptom severity and daily
functioning. Therefore we expect that a longer treatment period with clonidine
will improve not only positive symptom severity, but also notoriously treatment
resistant negative symptomatology. We also expect an improvement in cognitive
functioning and daily functioning.

The primary aim is to investigate whether six weeks augmentation with clonidine
of the antipsychotic treatment will reduce positive and negative symptomatology
of treatment resistant schizophrenia patients. Important secondary goals of
this project are to determine whether this treatment will improve cognitive
functioning and daily functioning in these treatment resistant schizophrenia
patients. Also, parameters of basic information processing, measured with EEG
will be assessed as a secondary outcome.

In a typical randomized clinical trial (RCT), a total of 50 patients with
schizophrenia with no or only partial response to clozapine will be randomized
over two arms: in one arm patients will receive an additional daily dose of
clonidine (50 µg) to their current antipsychotic treatment, while in the second
arm patients will receive placebo added to their medication. Both treatments
will be sustained for 6 weeks. In addition, 25 healthy controls will be
included matched on age and gender to evaluate the extent of the expected
effects in the patients, as well as to assess the impact of test-effects, since
these are notorious in particular for cognitive assessments e.g.: 2. We choose
a 6 weeks period to balance between rate of drop out and yet still being able
to detect improvements in quality of life: cognition, sensory filtering and
mismatch negativity are such basic human qualities, that improving them even
for a period as short as 6 weeks will definitely have a statistically
significant positive impact on the patient*s quality of life.
Following inclusion, baseline assessments will be made, which will be repeated
after periods of 3 and 6 weeks. To avoid too many influences of test-effects,
cognition will be assessed only at baseline and after 6 weeks. The healthy
controls will be assessed at these same intervals, but will receive no
treatment at all.

The main investigational product used in this study is clonidine, which is
approved for the treatment of several disorders including high blood pressure,
migraine and withdrawal symptoms that occur after stopping the use of opiates.

-25 patiënts will receive 50 micrograms clonidine once a day for six weeks,
added to their own antypsychotics which will preferably kept stable during
threatment period.
-25 patiënts will receive placebotablets once a day for six weeks, identical
looking to the clonidine tablets. Patiënts will continue their own
antipsychotica and these will preferably kept stable.
-25 healty controls will not undergo any treatment.

During the study, no invasive methods will be used. The total burden and risks
for the patients is based on the following factors:
1. Time investment: the complete study consists of 3 visits, with a total time
of 20 hours. A more detailled schedule of all protocol procedures can be found
in Table 1 of the protocol.
2. Side effects of clonidine. Considering that generally, side effects of
clondine are mild and considering that the dosage administered in our study
will be very low, no severe side effects can be expected.

Risks will be minimized through:
-elaborate in- and exclusion criteria
-implementation of appropriate, pro-active safety measures (e.g. strict
monitoring of onset and course of specific side effects)
-Applying specific "stopping rules", which means that in case patients seem to
develop specific side effects, they will be dropped out of the study, after
which appropriate follow-up takes place as well as treatment if necessary.

A complete consideration of risks and burden on one hand and benefits on the
other is prodded in section 13.2 "synthesis" of the structured risk analysis of
the protocol