ABSTRACT
The genotype of the receptor with which a particular drug interacts may be a between- subject factor that modifies the pharmacodynamic and consequently the therapeutic response to drugs. Subjects with A1 allele (Taq IA restriction fragment length polymorphism) of the gene encoding for the dopamine D2 receptor (DRD2) seem to express lower number of DRD2 compared to subjects who do not have this allele. We investigated whether subjects homozygous for the A1 allele of the DRD2 gene have decreased response to DRD2 stimulation by apomorphine when compared with those homozygous for the A2 allele. Two hundred and two Caucasian subjects were genotyped for DRD2 Taq IA polymorphism, 6.9 % had the genotype A1A1 and 65% A2A2. Nine homozygous subjects/group were selected for the apomorphine study. Five, 10 and 20 &mgr;g/kg of apomorphine were administered subcutaneously according to a randomized crossover design. The main pharmacodynamic criterion was the plasma growth hormone increase induced by apomorphine. Secondarily, we measured oral temperature responses and yawns in response to apomorphine. Plasma apomorphine concentrations were similar for the two matched and only genotypically different groups. Apomorphine dose-dependently increased serum growth hormone concentration, and significant effect of time, dose by time interaction but no effect of genotype or genotype by dose interaction was shown. Apomorphine decreased body temperature, significant effect of dose, time, dose by time interaction but no effect of genotype or genotype by dose interaction were observed. The number of apomorphine-induced yawns increased dose-dependently but no significant difference between groups occurred. Thus, in this study apomorphine-induced responses were not modified by DRD2 Taq IA polymorphism although the power of the study could be insufficient to detect subtle differences.
ABSTRACT
Alterations in thyroid axis are common in depression and subclinical hypothyroidism may predispose to recurrent depressive episodes and resistance to antidepressants. The same normal reference ranges are used in both depressive and non-psychiatric patients to detect hypothyroidism. We hypothesized that in depressive patients, serum TSH (thyrotropin) elevation within the normal reference range (>/= upper 25th percentile) may be related to patients' characteristics reflecting the severity of the depressive illness. We analysed, in a cross-sectional study, the relationship between serum TSH and serum-free thyroxine (T4) concentrations and different demographic and psychiatric characteristics in 94 depressive in-patients with DSM-III-R criteria for major depression. The frequency of subclinical hypothyroidism (normal serum T4, higher than normal serum TSH) was 5.3 %. In univariate analyses patients who had serum TSH concentrations >/= upper 25th percentile of the normal range were more likely to have recurrent depression, longer disease duration, higher number of episodes of major depression, higher number of previous suicide attempts and higher body mass index than those patients who had serum TSH concentrations < upper 25th percentile of the normal range (age-adjusted p<0.05). Stepwise logistic regression analysis showed that serum TSH >/= upper 25th percentile of the normal range was positively associated with recurrent depression (p=0.0001), presence of somatic disease condition (p=0.04), marital status (p=0.06) and number of suicide attempt (p=0.1). On the other hand, significantly higher serum TSH concentrations were observed in patients with recurrent depression, melancholia and associated somatic disease conditions. Correspondence analysis showed that serum TSH in the higher 25th percentile of the normal reference range projected together with the presence of melancholia, psychiatric and somatic disease conditions, severe major depressive episodes, recurrence of depressive episodes, prescription of at least two antidepressants or non-response to two antidepressants, and previous suicide attempts. Our study suggests that serum TSH concentration in the upper 25th percentile of the normal reference range may be associated with characteristics of severe major depression. Further prospective studies are needed to establish whether serum TSH concentration in the upper 25th percentile of the normal reference range is a contributory causal factor or a consequence of the severity of major depression.
