Antidopaminergic medication in healthy subjects provokes subjective and objective mental impairments tightly correlated with perturbation of biogenic monoamine metabolism and prolactin secretion

Abstract

Objectives

Off-label prescription of antipsychotics to patients without psychotic symptoms has become a routine matter for many psychiatrists and also some general practitioners. Nonetheless, little is known about the possibly detrimental effects of antidopaminergic medications on general psychopathology, subjective mental state, or a possible association with physiological parameters in nonpsychotic individuals.

Methods

In this randomized, single-blinded study, groups of healthy volunteers (n=18) received low doses of reserpine, aripiprazole, haloperidol, or placebo on 7 successive days. Relevant physiological parameters (plasma prolactin, concentrations of catecholamine metabolites in plasma, and 24-hour urine) and each subject’s mental state (Positive and Negative Syndrome Scale, Hamilton Rating Scale for Depression, visual analogue scale, Beck Depression Inventory II) were assessed at the start and end of the trial.

Results

Of the three active treatments, only reserpine caused a significant increase in some plasma- and urine-catecholamine metabolites, but all three medications evoked objective and subjective changes in general psychopathology scores, which correlated with individual increases in plasma homovanillic acid concentrations. Both objective and subjective impairments were significantly more pronounced in the subgroup with greatest increase of plasma prolactin. Subjects experiencing the most pronounced side effects under haloperidol, which compelled them to drop out, showed significantly higher prolactin concentration increases than those who tolerated haloperidol well.

Conclusion

We found consistent associations between altered markers of dopamine transmission and several objective and subjective mental impairments in healthy volunteers after 1 week’s treatment with antidopaminergic medications. These findings should draw attention to a more intensive risk–benefit evaluation in cases of off-label prescription of antipsychotic medications.

Keywords:

• catecholamine metabolites
• HVA
• prolactin
• dopamine
• reserpine
• aripiprazole
• halo-peridol
• off-label prescription

Acknowledgments

This study was supported by the START Program of the Medical Faculty of RWTH Aachen University and the International Research and Training Group (IRTG1328) of the German Research Foundation (DFG). Aripiprazole was kindly provided by Bristol-Myers Squibb GmbH and Co KGaA, Munich, Germany. The authors note assistance from Inglewood Biomedical Editing in preparing the manuscript. They further thank Andre Kirner and Ger Janssen for helpful suggestions.

Disclosure

TV has received grant support from Bristol-Myers Squibb. IV has served on the speakers’ bureaux of Bristol-Myers Squibb (New York, NY), Eli Lilly (Indianapolis, IN), and GlaxoSmithKline (London, UK). GG has served as a consultant for Allergan, Boehringer Ingelheim, Eli Lilly, Janssen-Cilag, Lundbeck, Ono Pharmaceuticals, Otsuka, Recordati, Roche, Servier, and Takeda, and served on the speakers’ bureaux of Eli Lilly, Janssen Cilag, Lundbeck, Neuraxpharm, Otsuka, Roche, Servier, and Trommsdorff. He has received grant support from Boehringer Ingelheim and Roche, and is cofounder of Pharma Image and Brainfoods GmbH. The other authors report no conflicts of interest in this work.