Treatment Response in Non-Affective Psychosis.

Approximately 30% of patients with non-affective psychotic disorder show
insufficient response to non-clozapine antipsychotic treatment. Therefore, it
is desirable to identify these patients early on by use of a clinical
algorithm. This algorithm is likely to be based on a number of biomarkers.
Potential biomarkers are striatal dopamine synthesis capacity (sDSC), glutamate
and gamma aminobutyric acid (GABA) concentrations in the anterior cingulate
cortex (ACC). sDSC can be measured by use of [18F]-DOPA Positron Emission
Tomography (PET). Glutamate and GABA concentrations in the ACC can be measured
by use of proton Magnetic Resonance Imaging (1H-MRI).

Using resting-state functional MRI Sarpal et al (Am J Psychiatry; 2016, volume
173, pp. 69-77) examined the relationship between (i) striatal connectivity
with other brain areas and (ii) response to antipsychotic drug. The results
showed that a greater connectivity between posterior regions and striatal
subdivisions is associated with a better response to antipsychotics, whereas,a
greater connectivity between frontal regions and striatal subregions was
associated with a worse response.

Interestingly, cannabis use is associated with an increased risk of psychosis.
The main constituent of cannabis, delta-9-tetrahydrocannabinol (THC), exerts
its psychotropic effect by binding to receptors of the endocannabinoid system
(ECS), and influences dopamine release. The evidence in support of
sensitisation of the mesolimbic dopamine system in the pathogenesis of
non-affective psychotic disorder is large. However, the relationships between
sDSC, glutamate and GABA concentrations in the ACC and blood levels of the
endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) have never
been examined.

A drawback of PET imaging is the use of radiotracers. Preferably,
treatment-resistant patients should be identified without using radioactivity.
One promising tool to do this, without inducing a radiation burden, is by use
of a neuromelanin-MRI (NM-MRI) sequence. However, it is unknown whether an
association exists between NM-MRI signal and sDSC. Therefore, validation of
NM-MRI as an indirect measurement of striatal functioning in schizophrenic
patients is necessary to develop a non-invasive algorithm to predict
treatment-response.
Understanding the relationships between the activity of various
neurotransmitter systems and treatment response is an important step in the
development of personalized treatment.

1) To compare between treatment responders, treatment non-responders, and
healthy controls: sDSC and GABA in the ACC;
2) To assess, in psychotic patients and healthy controls, whether AEA and 2-AG
plasma levels are associated with sDSC, and concentrations of glutamate and
GABA in the ACC;
3) To exploratory investigate, whether, NM-MRI signal is associated with
treatment response to non-clozapine antipsychotics (in patients) and with sDSC
(in patients and healthy controls).
4) Replicating Sarpal et al. (2017). Hypotheses: Greater connectivity between
posterior regions and striatal subdivisions is associated with a better
response to antipsychotics. Whereas, greater connectivity between frontal
regions and striatal subregions is associated with a worse response.

Prospective study

Participants will be assessed on four separate occasions:
- Baseline assessment (before or within 6 weeks after the start of
non-clozapine antipsychotic medication; total duration: 2h): evaluatin of
competence, screening for inclusion/exclusion criteria, informed consent, urine
drug test, and assessment of symptoms;
- Test day (before or within 9 weeks after the start of non-clozapine
antipsychotic medication; total duration: 2h): MRI scan, urine drug test,
determination of endocannabinoid plasma concentrations, fatty acid patterns,
TG, CRP and antipsychotic plasma concentrations. Furthermore, depressive
symptoms and factors that may influence the endocannabinoids will be assessed.
In a subgroup of 26 psychotic patients, an additional [18F]-DOPA PET scan will
be acquired. The PET scan will occur on the same day as the MRI scan, if
possible with the scanning facilities of the UMC Amsterdam. This will add three
hours to the visit. Otherwise, an additional visit will be scheduled;
- First follow-up (after 4-6 weeks of non-clozapine antipsychotic treatment at
adequate dose; total duration: 2h): diagnostic interview and assessment of
symptoms and determination of antipsychotic plasma concentration;
- Second follow-up (6 months after the start of non-clozapine antipsychotic
treatment; total duration: 1h): assessment of symptoms and substance use.
If applicable, treatment compliance will be evaluated together with the patient
during each occasion. The test day will take place at the UMC Amsterdam
(location AMC). The other assessments will take place at the mental healthcare
centre where the patient is under treatment. Total amount of time consuming for
the individual patient: 10 hours (in case of MRI and PET scans) or 7 hours (in
case of MRI scan only). Total duration of the study for the individual patient:
6 months.

Twenty healthy controls will be assessed on two separate occasions: (T1)
informed consent, screening, psychiatric interview, urine drug test, and
assessment of anxiety symptoms and medication use (total duration: 2h); (T2)
PET and MRI scans, urine drug test, evaluation of depressive symptoms and blood
sampling (total duration: 5h). Total amount of time consuming for the
individual subject: 7 hours. Total duration of the study for the individual
subject: 1 month.

Risks: The radiation dose is 4.1 mSv and falls within category IIb (minor to
intermediate). Benefits of the study: patients and healthy controls will not
benefit from participation. However, the obtained knowledge will contribute to
the development of a non-invasive algorithm to predict treatment-response and
may offer new starting points for the development of alternative treatments for
non-affective psychotic disorders.