A.J.W. Van der Does

Monoamine depletion in psychiatric and healthy populations: review

A number of techniques temporarily lower the functioning of monoamines: acute tryptophan depletion (ATD), alpha-methyl-para-tyrosine (AMPT) and acute phenylalanine/tyrosine depletion (APTD). This paper reviews the results of monoamine depletion studies in humans for the period 1966 until December 2002. The evidence suggests that all three interventions are specific, in terms of their short-term effects on one or two neurotransmitter systems, rather than on brain protein metabolism in general. The AMPT procedure is somewhat less specific, affecting both the dopamine and norepinephrine systems. The behavioral effects of ATD and AMPT are remarkably similar. Neither procedure has an immediate effect on the symptoms of depressed patients; however, both induce transient depressive symptoms in some remitted depressed patients. The magnitude of the effects, response rate and quality of response are also comparable. APTD has not been studied in recovered major depressive patients. Despite the similarities, the effects are distinctive in that ATD affects a subgroup of recently remitted patients treated with serotonergic medications, whereas AMPT affects recently remitted patients treated with noradrenergic medications. The evidence also suggests that ATD and APTD affect different cognitive functions, in particular different memory systems. Few studies investigated cognitive effects of the procedures in patients. Patients who are in remission for longer may also be vulnerable to ATD and AMPT, but the relationship with prior treatment is much weaker. For these patients, individual vulnerability markers are the more important determinants of depressive response, making these techniques potentially useful models of vulnerability to depression.

GENETIC MARKERS OF STRIATAL DOPAMINE PREDICT INDIVIDUAL DIFFERENCES IN DYSFUNCTIONAL, BUT NOT FUNCTIONAL IMPULSIVITY

Various psychiatric disorders are characterized by elevated levels of impulsivity. Although extensive evidence supports a specific role of striatal, but not frontal dopamine (DA) in human impulsivity, recent studies on genetic variability have raised some doubts on such a role. Importantly, impulsivity consists of two dissociable components that previous studies have failed to separate: functional and dysfunctional impulsivity. We compared participants with a genetic predisposition to have relatively high striatal DA levels (DAT1 9-repeat carriers, DRD2 C957T T/T homozygotes, and DRD4 7-repeat carriers) with participants with other genetic predispositions. We predicted that the first group would show high scores of dysfunctional, but not functional, self-reported impulsivity and greater difficulty in inhibiting a behavioral response to a stop-signal, a behavioral measure of impulsivity. In a sample of 130 healthy adults, we studied the relation between DAT1, DRD4, and C957T polymorphism at the DRD2 gene (polymorphisms related to striatal DA) and catechol-Omethyltransferase (COMT) Val158Met (a polymorphism related to frontal DA) on self-reported dysfunctional and functional impulsivity, assessed by the Dickman impulsivity inventory (DII), and the efficiency of inhibitory control, assessed by the stop-signal paradigm. DRD2 C957T T/T homozygotes and DRD4 7-repeat carriers indeed had significantly higher scores on self-reported dysfunctional, but not functional, impulsivity. T/T homozygotes were also less efficient in inhibiting prepotent responses. Our findings support the claim that dopaminergic variation affects dysfunctional impulsivity. This is in line with the notion that the over-supply of striatal DA might weaken inhibitory pathways, thereby enhancing the activation of, and the competition between responses.

A common and functional mineralocorticoid receptor haplotype enhances optimism and protects against depression in females

Mineralocorticoid (MR) and glucocorticoid receptors (GR) are abundantly expressed in the limbic brain and mediate cortisol effects on the stress-response and behavioral adaptation. Dysregulation of the stress response impairs adaptation and is a risk factor for depression, which is twice as abundant in women than in men. Because of the importance of MR for appraisal processes underlying the initial phase of the stress response we investigated whether specific MR haplotypes were associated with personality traits that predict the risk of depression. We discovered a common gene variant (haplotype 2, frequency ∼0.38) resulting in enhanced MR activity. Haplotype 2 was associated with heightened dispositional optimism in study 1 and with less hopelessness and rumination in study 2. Using data from a large genome-wide association study we then established that haplotype 2 was associated with a lower risk of depression. Interestingly, all effects were restricted to women. We propose that common functional MR haplotypes are important determinants of inter-individual variability in resilience to depression in women by differentially mediating cortisol effects on the stress system.

Omega-3 fatty acids (fish-oil) and depression-related cognition in healthy volunteers

Abstract Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation may be beneficial in the treatment of several psychiatric disorders, including depression. A small number of studies have suggested that there may also be cognitive and mood effects in healthy samples. The purpose of the present study was to investigate the effects of n-3 PUFA on depression-relevant cognitive functioning in healthy individuals. Fifty-four healthy university students were randomized to receive either n-3 PUFA supplements or placebo for 4 weeks in a double-blind design. The test battery included measures of cognitive reactivity, attention, response inhibition, facial emotion recognition, memory and risky decision-making. Results showed few effects of n-3 PUFAs on cognition and mood states. The n-3 PUFA group made fewer risk-averse decisions than the placebo group. This difference appeared only in non-normative trials of the decision-making test, and was not accompanied by increased impulsiveness. N-3 PUFAs improved scores on the control/perfectionism scale of the cognitive reactivity measure. No effects were found on the other cognitive tasks and no consistent effects on mood were observed. The present findings indicate that n-3 PUFA supplementation may have a selective effect on risky decision making in healthy volunteers, which is unrelated to impulsiveness.

Serotonin transporter gene, childhood emotional abuse and cognitive vulnerability to depression

Meta‐analyses evaluating the association between the serotonin transporter polymorphism (5‐HTTLPR) with neuroticism and depression diagnosis as phenotypes have been inconclusive. We examined a gene–environment interaction on a cognitive vulnerability marker of depression, cognitive reactivity (CR) to sad mood. A total of 250 university students of European ancestry were genotyped for the 5‐HTTLPR, including SNP rs25531, a polymorphism of the long allele. Association analysis was performed for neuroticism, CR and depression diagnosis (using a self‐report measure). As an environmental pathogen, self‐reported history of childhood emotional abuse was measured because of its strong relationship with depression. Participants with the homozygous low expressing genotype had high CR if they had experienced childhood emotional maltreatment but low CR if they did not have such experience. This interaction was strongest on the Rumination subscale of the CR measure. The interaction was not significant with neuroticism or depression diagnosis as outcome measures. Our results show that 5‐HTTLPR is related to cognitive vulnerability to depression. Our findings provide evidence for a differential susceptibility genotype rather than a vulnerability genotype, possibly because of the relatively low levels of abuse in our sample. The selection of phenotype and environmental contributor is pivotal in investigating gene–environment interactions in psychiatric disorders.

Symptom dimensions and cognitive and social functioning in recent-onset schizophrenia.

The relationships among symptoms, cognitive functioning and social functioning were investigated in 60 patients with recent-onset schizophrenia. Positive symptoms were unrelated to cognitive measures. Disorganization and depressive symptoms were correlated significantly with Card Sorting performance. Furthermore, only negative symptoms were correlated significantly with social functioning. These results replicate earlier studies with chronic and mixed samples, and support the validity of disorganization as a separate symptom dimension. In contrast to most previous studies, no significant correlations were found between negative symptoms and cognitive measures. However, some evidence was found for a non-linear association between negative symptoms had several cognitive measures. The variation explained by a curvilinear model was not high, but for some cognitive measures this model was clearly superior to a linear model. If replicated, this finding supports the position that cross-sectionally measured negative symptoms cannot be viewed as a unitary concept.

Symptoms, cognitive and social functioning in recent-onset schizophrenia: A longitudinal study

The relationships among symptoms, cognitive functioning and social functioning were investigated in patients with schizophrenia over a period of 15 months. Patients with a mood disorder, a normal control group and a sample of parents of the schizophrenic patients also completed the cognitive tests. In the schizophrenia sample, only disorganisation was correlated with cognitive performance, which was interpreted as further evidence that disorganisation is a separate symptom dimension of schizophrenia. Against expectations, with two of three measurements no significant correlations were found between negative symptoms and cognitive performance. With these two measurements, however, a curvilinear association between negative symptoms and cognitive performance was observed, suggesting that negative symptoms are not a unitary concept. Finally, tentative evidence could be obtained for speed of information processing and selective attention as markers for vulnerability, although the latter is not specific for schizophrenia.

Relationships among 5-HTT Genotype, Life Events and Gender in the Recognition of Facial Emotions

Accumulating evidence has shown that a polymorphism in the promoter region of the serotonin-transporter (5-HTTLPR) modulates neural activation during the perceptual processing of emotional facial expressions. Furthermore, behavioral research has shown that attentional bias for negative information is increased in s allele carriers. We examined the interactions among 5-HTTLPR (including SNP rs25531), life events and gender on the detection of facial emotions. We found a main effect of genotype, as well as moderating effects of childhood emotional abuse (CEA) and recent life events (RLE). S homozygous participants recognized negative facial expressions at a lower intensity than the other genotype groups. This effect was more evident in female participants and in participants who had experienced life events. The 5-HTTLPR genotype affects facial emotional perception, a process which is linked to a neurobiological response to threat and vulnerability to emotional disorders.

Mineralocorticoid receptor haplotype oral contraceptives and emotional information processing.

BACKGROUND Oral contraceptives (OCs) affect mood in some women and may have more subtle effects on emotional information processing in many more users. Female carriers of mineralocorticoid receptor (MR) haplotype 2 have been shown to be more optimistic and less vulnerable to depression. AIM To investigate the effects of oral contraceptives on emotional information processing and a possible moderating effect of MR haplotype. METHODS Cross-sectional study in 85 healthy premenopausal women of West-European descent. RESULTS We found significant main effects of oral contraceptives on facial expression recognition, emotional memory and decision-making. Furthermore, carriers of MR haplotype 1 or 3 were sensitive to the impact of OCs on the recognition of sad and fearful faces and on emotional memory, whereas MR haplotype 2 carriers were not. LIMITATIONS Different compounds of OCs were included. No hormonal measures were taken. Most naturally cycling participants were assessed in the luteal phase of their menstrual cycle. CONCLUSIONS Carriers of MR haplotype 2 may be less sensitive to depressogenic side-effects of OCs.

The relationships between expressed emotion, affective style and communication deviance in recent-onset schizophrenia.

The relationships between expressed emotion (EE), affective style (AS) and communication deviance (CD) were studied during hospitalization and after discharge. EE was measured with both the Camberwell Family Interview (CFI) and the Five‐Minutes Speech Sample (FMSS). The study subjects were patients with recent‐onset schizophrenia and related disorders, who were consecutively admitted to an in‐patient unit for adolescents, and their parents. The results revealed that CFI/EE was significantly correlated with AS criticism scores during hospitalization, but did not predict AS scores after discharge. FMSS/EE correlated significantly with AS criticism when both measures were administered after discharge. During hospitalization, FMSS/EE was not significantly correlated with AS. No consistent relationship was found between CD and both affective factors (EE and AS). It is concluded that EE and AS overlap with regard to level of criticism when both measures are administered over a short period of time and independent of the time of assessment. In addition, the results indicate that affective and communication factors identify independent family attributes.