Amphetamine-Induced Dopamine Release Predicts 1-Year Outcome in First-Episode Psychosis: A Naturalistic Observation

Abstract

Background and hypothesis: The dopamine theory of schizophrenia suggests that antipsychotics alleviate symptoms by blocking dopamine D2/3 receptors, yet a significant subset of patients does not respond adequately to treatment. To investigate potential predictors, we evaluated d-amphetamine-induced dopamine release and 1-year clinical outcomes in 21 antipsychotic-naive patients with first-episode schizophrenia.

Study design: Twenty-one antipsychotic-naive patients (6 female) underwent dopamine D2/3 receptor radioligand [11C]-(+)-PHNO positron emission tomography. For estimating dopamine release, scans were performed with and without d-amphetamine pretreatment. The Positive and Negative Syndrome Scale was performed at regular intervals over 1 year while receiving treatment in a naturalistic setting (Clinical Trial Registry: EUDRACT 2010-019586-29).

Study results: A group analysis revealed no significant differences in d-amphetamine-induced dopamine release between patients with or without clinically significant improvement. However, d-amphetamine-induced dopamine release in ventral striatum was significantly associated with reductions in positive symptoms (r = 0.54, P = .04; uncorrected P-values); release in globus pallidus correlated with a decrease in PANSS negative (r = 0.58, P = .02), general (r = 0.53, P = .04), and total symptom scores (r = 0.063, P = .01). Higher dopamine release in substantia nigra/ventral tegmental area predicted larger reductions in general symptoms (r = 0.51, P = .05). Post-amphetamine binding in putamen correlated positively with negative symptom scores at baseline (r = 0.66, P = .005) and throughout all follow-up visits.

Conclusions: These exploratory results support a relationship between d-amphetamine-induced dopamine release and the severity and persistence of symptoms during the first year of psychosis.

Keywords: PET; PHNO; dopamine release; patients; psychosis; schizophrenia; symptoms.

Fig. 1.

The illness course of all 21 patients with first-episode psychosis (FEP) quantified with the PANSS scale. Scores of the positive, negative, and general subdomains are shown as well as the total PANSS score. Patients without an adequate treatment are displayed (n = 7) while patients, who accepted an antipsychotic treatment regime (n = 14) are shown. The 2 patients, who were lost to follow-up are included in this plot.

Fig. 2.

Sixteen patients (5 patients with improvement, 11 without significant improvement). From the group without improvement 5 did not accept adequate antipsychotic treatment and 6 had sufficient antipsychotic medication. Although not significant, there is a pattern of a higher d-amphetamine-induced dopamine release in patients with significant clinical improvement at month 3.

Fig. 3.

Correlations between d-amphetamine-induced dopamine release and symptom reductions of each PANSS subdomain. * indicates P < .05.

Fig. 4.

Binding of [¹¹C]-(+)-PHNO to dopamine D_2/3 receptors after d-amphetamine in the right putamen and PANSS negative symptom scores in antipsychotic-naive patients with FEP before initiation of treatment (baseline) and during a 1-year follow-up under naturalistic treatment conditions; patients with adequate adherence to antipsychotic treatment and patients with no or minimal adherence to antipsychotic treatment are shown.