Clozapine but not lithium reverses aberrant tyrosine uptake in patients with bipolar disorder

Abstract

Rationale: Availability of the dopamine and noradrenaline precursor tyrosine is critical for normal functioning, and deficit in tyrosine transport across cell membrane and the blood-brain barrier has been reported in bipolar disorder and schizophrenia. Clozapine and lithium are two psychoactive agents used to treat psychosis, mood disorders and suicidal behavior, but their mechanism of action remains largely unknown.

Objective: To characterize immediate and delayed differences in tyrosine uptake between healthy controls (HC) and bipolar patients (BP) and see if these differences could be normalized by either clozapine, lithium or both. A second objective was to see if clozapine and lithium have additive, antagonistic or synergistic effects in this.

Method: Fibroblasts from five HC and five BP were incubated for 5 min or 6 h with clozapine, lithium, or combination of both. Radioactive labelled tyrosine was used to quantify tyrosine membrane transport.

Results: There was significantly reduced tyrosine uptake at baseline in BP compared to HC, a deficit that grew with increasing incubation time. Clozapine selectively increased tyrosine uptake in BP and abolished the deficit seen under baseline conditions, while lithium had no such effect. Combination treatment with clozapine and lithium was less effective than when clozapine was used alone.

Conclusions: There was significant deficit in tyrosine transport in BP compared to HC that was reversed by clozapine but not lithium. Clozapine was more effective when used alone than when added together with lithium. Potential clinical implications of this will be discussed.

Keywords: Bipolar disorder; Clozapine; Dopamine; Fibroblasts; Lithium; Noradrenaline; Pathophysiology; Tyrosine.

Fig. 1

Repeated measures ANOVA, p-values Bonferroni adjusted for multiple comparison. Clozapine significantly reduced tyrosine uptake (nmol/5 min × mg protein) in healthy controls at 1.0 μmol/L (p = 0.008), but not at 0.5 μ mol/L (p = 0.98). At 1.5 μmol/L, clozapine initially significantly reduced tyrosine uptake by roughly 10%, but this did not survive Bonferroni correction for multiple comparison (p = 0.16). ⁎⁎ = p ≤ 0.01

Fig. 2

Tyrosine uptake (nmol/5 min x mg protein) in the absence of psychoactive drugs at 5-min and 6-h drug incubation times. Mann-Whitney U test showed significant deficit in bipolar patients compared to healthy controls for both the 5-min (−15.5%; p = 0.044) and 6-h (−31.2%; p < 0.001) incubation times. Shown is median ± IQR. The 6-h but not the 5-min drug incubation time survived Bonferroni correction for multiple comparison

Fig. 3

Tyrosine uptake (nmol/5 min × mg protein) in healthy controls and bipolar patients under different conditions as indicated during 5-min (A) and 6-h (B) drug incubation times. Shown is median ± IQR. Kruskal-Wallis test with p-values adjusted for multiple comparison with Bonferroni correction: NS = not significant; * = p < 0.05; ** = p < 0.01; *** = p < 0.001. Bipolar patients had significantly lower tyrosine uptake than healthy controls except in the presence of clozapine. The initial between-group differences seen at 5-min incubation time (A) did not survive Bonferroni correction for multiple comparison. Clo+Lit = Clozapine+Lithium