R.J. Verkes

Neurosteroids in depression: a review.

Abstract Rationale. A deregulation in concentrations of the neurosteroids (allo)pregnanolone and 3α,5α-tetrahydrodeoxycorticosterone (3α,5α-TH DOC) has been found in depressed patients. These levels normalize following treatment with selective serotonin reuptake inhibitors (SSRIs). Furthermore, administration of the neurosteroid dehydroepiandrosterone (DHEA) to depressed patients is associated with an improvement in the symptoms of depression. Objective. The aim of the present review is to clarify the mechanisms whereby neurosteroids, particularly allopregnanolone and DHEA, are involved in depression and to discuss the effect of SSRIs on allopregnanolone concentration. Methods. Literature on preclinical and clinical research has been analyzed in relation to the pathophysiology of depression. Results. Decreased plasma and cerebrospinal fluid concentrations of allopregnanolone in depressed patients increase to normal levels following effective psychopharmacological treatment. This might either be a physiological aspect of improvement in the symptoms of depression or a pharmacologically induced alteration. Several findings support the hypothesis of an antidepressant effect of allopregnanolone. These include an antidepressant effect demonstrated in an animal model of depression and a suppressing effect on corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) gene expression. SSRIs increase levels of allopregnanolone, but this effect is not confined to this class of drugs alone. The beneficial effect of DHEA administration in depressed patients might result from its sigma 1 receptor-mediated enhancement of noradrenaline and serotonin neurotransmission, antiglucocorticoid effects, and cognition enhancing effects. Conclusions. Indirect genomic (allopregnanolone) and non-genomic (allopregnanolone and DHEA) mechanisms are involved in the neurosteroidogenic pathophysiology of depression. Clinical studies in homogeneous groups of non-pharmacologically treated depressed patients are required to elucidate this relationship further.

Progesterone selectively increases amygdala reactivity in women

The acute neural effects of progesterone are mediated by its neuroactive metabolites allopregnanolone and pregnanolone. These neurosteroids potentiate the inhibitory actions of γ-aminobutyric acid (GABA). Progesterone is known to produce anxiolytic effects in animals, but recent animal studies suggest that pregnanolone increases anxiety after a period of low allopregnanolone concentration. This effect is potentially mediated by the amygdala and related to the negative mood symptoms in humans that are observed during increased allopregnanolone levels. Therefore, we investigated with functional magnetic resonance imaging (MRI) whether a single progesterone administration to healthy young women in their follicular phase modulates the amygdala response to salient, biologically relevant stimuli. The progesterone administration increased the plasma concentrations of progesterone and allopregnanolone to levels that are reached during the luteal phase and early pregnancy. The imaging results show that progesterone selectively increased amygdala reactivity. Furthermore, functional connectivity analyses indicate that progesterone modulated functional coupling of the amygdala with distant brain regions. These results reveal a neural mechanism by which progesterone may mediate adverse effects on anxiety and mood.

Effects of antipsychotic and antidepressant drugs on action monitoring in healthy volunteers.

Humans need to monitor their actions continuously to detect errors as fast as possible and to adjust their performance to prevent future errors. This process of action monitoring can be investigated by measuring the error-related negativity (ERN), an ERP component elicited immediately after an error. In the current study, we investigated action monitoring after administration of the classic antipsychotic haloperidol (2.5 mg), the atypical antipsychotic olanzapine (10 mg), and the antidepressant paroxetine (20 mg), a selective serotonin reuptake inhibitor. Healthy volunteers (N = 14) were administered the three compounds and placebo in a randomized, double-blind, single-dose, four-way cross-over design. All participants performed a speeded two-choice reaction task, while event-related potentials and behavioral measurements were obtained. Both haloperidol and olanzapine significantly reduced ERN amplitudes. After paroxetine, the ERN was not different from placebo. N2 congruency effects were not affected by treatment condition. Only olanzapine demonstrated behavioral effects, namely a slowing of responses, an increase in error rates, and the absence of performance adjustments. The attenuated ERNs after the dopamine antagonist haloperidol are in line with the presumed role of dopamine in action monitoring. Haloperidol is thought to block dopaminergic signaling, thus reducing ERN amplitudes. On the other hand, the effects of olanzapine are mainly caused by its sedative side effects, leading to a decline in motivation and appraisal of errors. Finally, the absence of any effects after paroxetine suggests that serotonin transmission does not play a direct role in regulating mechanisms related to action monitoring.

Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3,4-methylenedioxymethamphetamine) administration

Abstract MDMA (3,4-methylenedioxymethamphetamine or “ecstasy”) is a recreationally used drug with remarkable and characteristic prosocial effects. In spite of abundant attention in the scientific literature, the mechanism of its prosocial effects has not been elucidated in humans. Recently, research in animals has suggested that the neuropeptide oxytocin may induce these effects. In a double blind, randomized, crossover, and placebo-controlled study in 15 healthy volunteers we assessed blood oxytocin and MDMA concentrations and subjective prosocial effects after oral administration of 100 mg MDMA or placebo. MDMA induced a robust increase of blood oxytocin concentrations and an increase of subjective prosocial feelings. Within subjects, the variations in these feelings were significantly and positively correlated with variation in oxytocin levels, and the correlations between these feelings and oxytocin were significantly stronger than those between these feelings and blood MDMA levels. MDMA induces oxytocin release in humans, which may be involved in the characteristic prosocial effects of ecstasy.

Effects of PhD examination stress on allopregnanolone and cortisol plasma levels and peripheral benzodiazepine receptor density

Peripheral benzodiazepine receptor (PBR) density in blood platelets and plasma allopregnanolone concentration in humans were determined following acute stress as represented by PhD examination. Fifteen healthy PhD students participated. Heart rate, blood pressure, plasma allopregnanolone, plasma cortisol, and PBR density were measured at different time points. Allopregnanolone and cortisol concentration and PBR density were significantly increased during examination. A positive correlation between allopregnanolone and PBR density was found.

Early and Late Components of Error Monitoring in Violent Offenders with Psychopathy

BACKGROUND One of the most recognizable features of psychopathy is the reduced ability to successfully learn and adapt overt behavior. This might be due to deficient processing of error information indicating the need to adapt controlled behavior. METHODS Event-related potentials (ERPs) and behavioral components of error-monitoring processes were investigated in 16 individuals with psychopathy and in 18 healthy subjects. A letter version of the Eriksen flanker task was used in two conditions. The first condition (normal condition) required participants to press one of two buttons depending on the identity of the target stimulus. The second condition (signaling condition) required them to signal each time they had committed an error by making a second press on a signaling button. Early stages of error monitoring were investigated by using the error-related negativity (ERN/Ne) and post-error slowing as indexes. Later stages were explored by examining the error positivity (Pe) and signaling rates. RESULTS Both groups showed similar ERN amplitudes and amounts of post-error slowing. The psychopathic group exhibited both reduced Pe amplitudes and diminished error-signaling rates compared with the control group. CONCLUSIONS Individuals with psychopathy show intact early error processing and automatic behavioral adaptation but have deficits in later stages of error processing and controlled behavioral adaptation. This is an indication that individuals with psychopathy are unable to effectively use error information to change their behavior adequately.

Human cognitive flexibility depends on dopamine D2 receptor signaling

RationaleAccumulating evidence indicates that the cognitive effects of dopamine depend on the subtype of dopamine receptor that is activated. In particular, recent work with animals as well as current theorizing has suggested that cognitive flexibility depends on dopamine D2 receptor signaling. However, there is no evidence for similar mechanisms in humans.ObjectivesWe aim to demonstrate that optimal dopamine D2 receptor signaling is critical for human cognitive flexibility.MethodsTo this end, a pharmacological pretreatment design was employed. This enabled us to investigate whether effects of the dopamine receptor agonist bromocriptine on task-set switching were abolished by pretreatment with the D2 receptor antagonist sulpiride. To account for individual (genetic) differences in baseline levels of dopamine, we made use of a common variable number of tandem repeat (VNTR) polymorphism in the 3′-untranslated region of the dopamine transporter gene, DAT1.ResultsBromocriptine improved cognitive flexibility relative to placebo, but only in subjects with genetically determined low levels of dopamine (n = 27). This beneficial effect of bromocriptine on cognitive flexibility was blocked by pretreatment with the selective dopamine D2 receptor antagonist sulpiride (n = 14).ConclusionsThese results provide strong evidence in favor of the hypothesis that human cognitive flexibility implicates dopamine D2 receptor signaling.

Interaction between dopamine D2 receptor genotype and parental rule-setting in adolescent alcohol use: evidence for a gene-parenting interaction.

Association studies investigating the link between the dopamine D2 receptor gene (DRD2) and alcohol (mis)use have shown inconsistent results. This may be due to lack of attention for environmental factors. High levels of parental rule-setting are associated with lower levels of adolescent alcohol use and delay of initiation of drinking. We tested whether DRD2 TaqI A (rs1800497) genotype interacts with alcohol-specific parenting practices in predicting the uptake of regular adolescent alcohol use. Non-regular drinkers were selected from a Dutch, nationwide sample of 428 adolescents (mean age 13.4 years at baseline) and participated in a prospective, community-based study with three annual waves. Parental rule-setting was directly and inversely related to adolescent alcohol use over time. For DRD2 genotype no significant main effect was found. DRD2 genotype interacted with parental rule-setting on adolescent alcohol use over time: adolescents, with parents highly permissive toward alcohol consumption and carrying a genotype with the DRD2 A1 (rs1800497T) allele, used significantly more alcohol over time than adolescents without these characteristics. The DRD2 genotype may pose an increased risk for alcohol use and abuse, depending on the presence of environmental risk factors, such as alcohol-specific parenting.

Treatment of unipolar psychotic depression: a randomized, double-blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine.

Wijkstra J, Burger H, van den Broek WW, Birkenhäger TK, Janzing JGE, Boks MPM, Bruijn JA, van der Loos MLM, Breteler LMT, Ramaekers GMGI, Verkes RJ, Nolen WA. Treatment of unipolar psychotic depression: a randomized, double‐blind study comparing imipramine, venlafaxine, and venlafaxine plus quetiapine.

A serotonin transporter polymorphism (5-HTTLPR) predicts the development of adolescent alcohol use

BACKGROUND Because the effects of susceptibility genes on alcohol use may differ as a function of age throughout adolescence and young adulthood, prospective study designs, in addition to cross-sectional ones are needed in genetic association studies. The short, low activity allele of a polymorphism (5-HTTLPR) in the serotonin transporter gene (SLC6A4) has been related to alcohol dependence. In the current study we tested whether 5-HTTLPR genotype was associated with adolescent alcohol use both cross-sectionally and longitudinally. METHODS Non-regular drinkers (n=202) were selected from Dutch, nationwide sample of adolescents (mean age 13.4 at baseline) who were assessed across five annual waves. Latent growth curve modeling was applied to examine individual development of alcohol use over time, by estimating the initial level of alcohol use at Wave 2 (intercept), and the rate of change in alcohol use across time (slope). RESULTS The 5-HTTLPR short allele predicted adolescents growth (slope) in alcohol use over time. Adolescents with the 5-HTTLPR short allele showed larger increase in alcohol consumption than those without the 5-HTTLPR short allele. 5-HTTLPR genotype was not related to the initial level (intercept) of alcohol consumption. In all analyses we controlled for sex and personality. CONCLUSIONS To gain more insight into the etiological role of genetic determinants of adolescent alcohol use, developmental approaches that distinguish between onset and continuation of drinking should be applied.