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

Figures & data

Table 1 Demographic data concerning age, sex proportion, BMI, and education in the different groups

Treatment group	n	Age (mean ± SD)	Female:male proportion	BMI	Education, years (mean ± SD)	Estimated IQ (mean ± SD)
Aripiprazole	18	25.6±6.5	11:7	24.4±4.5	15.9±2.1	123.8±18.4
Haloperidol	18	27.2±6.1	8:10	23.1±2.2	15.8±2.2	115.4±13.8
Reserpine	18	27.7±7.6	8:10	25.7±4.3	15.7±3.6	117.9±15.3
Placebo	18	24.6±3.9	11:7	23.2±2.5	16.8±2.6	114.3±14.7
All	72	26.3±6.2	38:34	24.1±3.6	16.0±2.7	117.9±15.8

Note: For intelligence estimation, the German language multiple-choice test of verbal crystallized premorbid intelligence (Lehrl et al, 1995¹¹²) was used.

Abbreviation: BMI, body-mass index.

Table 2 Concentrations of catecholamine metabolites (ng/mL) in plasma (p) and urine (u) (ng/day)

Plasma
	n	Day 1	Day 8	Δ% pHVA	RM ANOVA, time × group	Post hoc
		pHVA	pHVA
Placebo	18	13.84±6.1	14.24±6	2.2±6.8	F3,61 =0.45, P=0.717	NS
Aripiprazole	18	16.73±5.93	16.45±5.24	−1.7±11.6
Haloperidol	11	13.51±5.4	15.21±4.3	12.6±2.4
Reserpine	18	15.7±13.4	18.5±7.7	17.8±41.4
	n	pHIAA	pHIAA	Δ% pHIAA	RM ANOVA, time × group	Post hoc
Placebo	18	6.55±3.3	7.27±3.7	10.1±12.1	F3,61=1.5, P=0.217	NS
Aripiprazole	18	8.26±4.67	7.53±3.77	−8.8±19.3
Haloperidol	11	5.05±1.5	5.71±2.6	12.9±1.9
Reserpine	16	7.2±4.2	5.5±2.9	−23.6±3.3
	n	pMHPG	pMHPG	Δ% pMHPG	RM ANOVA, time × group	Post hoc
Placebo	18	5.66±2.23	5.55±2.11	−1.5±2.2	F3,59=5.95, P=0.001**	NS
Aripiprazole	16	4.98±2.86	5.58±2.56	12.1±10.5		NS
Haloperidol	11	6.75±3.9	6.14±3.5	−9.1±8.2		NS
Reserpine	18	4.06±2.14	6.3±2.9	55.2±35.5		P=0.001**
Urine
	N	Day 1	Day 8	Δ% uHVA	RM ANOVA, time × group	Post hoc
		uHVA	uHVA
Placebo	18	29.07±8.5	25.8±9.7	−11.2±5.3	F3,61=3.82, P=0.014*	NS
Aripiprazole	18	24.67±13.45	28.14±11.7	14.1±13		NS
Haloperidol	11	30.9±10.4	32.16±10	4.1±3.3		NS
Reserpine	18	24.3±9.2	37.98±13.73	56.3±40.4		P<0.001**
	N	uHIAA	uHIAA	Δ% uHIAA	RM ANOVA, time × group	Post hoc
Placebo	18	26.0±9.7	23.9±8.9	−8.1±7.2	F3,61=0.69, P=0.564	NS
Aripiprazole	18	22.29±12.6	23.27±8.5	4.4±3.1
Haloperidol	11	29.0±15.8	21.45±6.9	−26.1±19.8
Reserpine	18	24.48±12.5	20.33±8.9	16.9±11.3
	N	uVMA	uVMA	Δ% uVMA	RM ANOVA, time × group	Post hoc
Placebo	18	20.2±6.8	19.4±8.1	−4.1±2.1	F3,61=4.59, P=0.006**	NS
Aripiprazole	18	19.85±7.7	20.1±10.3	1.3±2.5		NS
Haloperidol	11	23.4±8.4	21.1±6.6	−9.8±7.6		NS
Reserpine	18	16.6±7.4	25.5±11.5	53.6±42.5		P=0.006**

Notes:

* P<0.05;

** P<0.01. Before (day 1) and after the 7-day antidopaminergic intervention (day 8) in the four groups, outlined as means ± SD. The mean extent of concentration change after the medication period relative to day 1 is outlined as Δ% ([{concentration measured on day 8 – concentration measured on day 1}/concentration measured on day 1] ×100).

Abbreviations: HVA, homovanillic acid; RM ANOVA, repeated-measures analysis of variance; HIAA, hydroxyindoleacetic acid; MHPG, 3-methoxy-4-hydroxyphenylglycol; VMA, vanillylmandelic acid.

Figure 1 Changes in monoamine metabolite concentrations after the 7-day medication period.

Notes: (A) P=0.001; (B) P=0.009; (C) P=0.006.
Abbreviations: HVA, homovanillic acid; MHPG, 3-methoxy-4-hydroxyphenylglycol; VMA, vanillylmandelic acid.

Table 3 Correlations among catecholamine metabolites in plasma and urine, scales for third-party assessment, and subjective assessment of some aspects of the mental condition

	HVA (plasma)	5-HIAA (plasma)	MHPG (plasma)	HVA (urine)	5-HIAA (plasma)	VMA (urine)
PANNS total
r	0.51**	NS	NS	NS	NS	NS
P	<0.001**,#
R^2	0.27
BCa 95% CI	0.25–0.70
PANSS cognitive
r	0.49	NS	NS	0.30	NS	NS
P	0.001**,#			0.045*
R^2	0.26			0.09
BCa 95% CI	0.32–0.66			−0.01 to 0.15
PANSS depressive
r	0.37	NS	NS	NS	NS	NS
P	0.01*
R^2	0.14
BCa 95% CI	0.02–0.63
HRSD
r	0.39	NS	NS	NS	NS	NS
P	0.007*
R^2	0.15
BCa 95% CI	0.17–0.61
BDI
r	0.313	NS	NS	NS	NS	NS
P	0.03
R^2	0.09
BCa 95% CI	0.004–0.57
VAS ability to concentrate
r	−0.48	−0.36	NS	NS	NS	NS
P	0.001**,#	0.015*
R^2	0.23
BCa 95% CI	−0.65 to −0.31	−0.53 to −0.20
VAS general well-being
r	−0.44	−0.46	NS	NS	NS	NS
P	0.002**,#	0.002**,#
R^2	0.19	0.21
BCa 95% CI	−0.64 to 0.22	−0.62 to −0.3
VAS fatigue
r	0.37	NS	NS	NS	NS	NS
P	0.011*
R^2	0.14
BCa 95% CI	0.14–0.61
VAS motivation
r	NS	NS	NS	NS	NS	NS
P
R^2
BCa 95% CI
VAS drive
r	−0.34	NS	NS	NS	NS	NS
P	0.021*
R^2	0.12
BCa 95% CI	−0.62 to −0.05

Notes:

* P<0.05;

** P<0.01;

**,# correlations remaining significant after Bonferroni correction (corrected significance level for ten scores and six metabolites P=0.003). Scales for third-party assessment (PANSS and HRSD) and assessment of mental condition (VAS and BDI) in the verum group measured on day 8 (24 hours after cessation of antidopaminergic intervention). PANSS subscales defined by the Lindenmayer et al model⁵² were analyzed separately.

Abbreviations: HVA, homovanillic acid; RM ANOVA, repeated-measures analysis of variance; HIAA, hydroxyindoleacetic acid; MHPG, 3-methoxy-4-hydroxyphenylglycol; VMA, vanillylmandelic acid; PANSS, Positive and Negative Syndrome Scale; HRSD, Hamilton Rating Scale for Depression; VAS, visual analogue scale; BDI, Beck Depression Inventory; BC_a, bias corrected and accelerated; NS, not significant.

Figure 2 Prolactin (Prl) changes versus scales for third-party and subjective assessment.

Abbreviations: PANSS, Positive and Negative Syndrome Scale; HRSD, Hamilton Rating Scale for Depression; BDI, Beck Depression Inventory; VAS, visual analogue scale.

Table 4 Prolactin changes vs scales for third-party and subjective assessment

	Prolactin increase <50% (n=19)	Prolactin increase >50% (n=35)	One-way ANCOVA
PANSS total	41.2±9.2	53.5±12.3	F1,51=14.45, P<0.001
PANSS cognitive	7.4±2.9	9.3±2.7	F1,51=5.6, P=0.022
PANSS depressive	5.4±0.8	8.5±3.7	F1,51=13.1, P=0.001
HRSD	3.6±3.9	8.3±6.9	F1,51=7, P=0.01
BDI	1.3±1.9	4.3±4.9	F1,51=7.4, P=0.009
VAS ability to concentrate	64.1±25.9	42.7±27.7	F1,51=7.5, P=0.008
VAS general well-being	64.8±26.8	48.2±25.9	F1,51=4.9, P=0.03
VAS fatigue	47.1±28.6	56.7±24.6	F1,51=1.6, P=0.217
VAS motivation	64.4±23.4	46.9±25.8	F1,51=5.1, P=0.028
VAS drive	66.7±20.7	44.3±26.2	F1,51=10.1, P=0.003

Abbreviations: ANCOVA, analysis of covariance; PANSS, Positive and Negative Syndrome Scale; HRSD, Hamilton Rating Scale for Depression; BDI, Beck Depression Inventory; VAS, visual analogue scale.

Table 5 Prolactin concentrations (mU/L) before and after 7-day medication period

Treatment group	Baseline	After medication period	Difference
Placebo	211.6±113.4	196.1±85.6	−15.4±66
Aripiprazole	160.9±65	189.6±209.6	28.7±219.1
Haloperidol	177.2±74.6	350.7±202.6	173.5±177.1
Completers (n=11)	204.5±87.3	277.7±155.5	73.3±109.5
Dropouts (n=7)	139.1±28.6	360.6±98.7	221.43±87.7
Reserpine	149.6±80.2	540.3±280.8	390.7±263.7

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