Catechol-o-methyltransferase polymorphism and susceptibility to major depressive disorder modulates psychological stress response.

OBJECTIVES: The stress response is related to both physiological and psychological factors and is strongly marked by a neuroendocrine component. Genetic factors are believed to underlie individual differences in the degree of stress resilience and thereby contribute in determining susceptibility to stress-related pathologies like major depressive disorder (MDD). Little, however, is known about the genetic influence on the endocrine and behavioural stress response in relation to MDD. METHODS: Here, we sought to examine the effects of the catechol-o-methyltransferase polymorphism on psychological stress in three groups of individuals with different degrees of susceptibility to MDD (i.e. healthy controls, healthy high risk probands to MDD and those suffering from MDD). This genotype is involved in the metabolism of catecholamines (dopamine, norepinephrine and epinephrine). RESULTS: Allelic variations of this polymorphism were found to influence the degree of subjective stress experience and plasma epinephrine stress response. Interactions between catechol-o-methyltransferase polymorphism and diagnostic group in measures of plasma epinephrine, cortisol and subjective responses to psychological stress were also found, with the influence of the different alleles on these measures differing between healthy controls relative to MDD patients and high risk probands. CONCLUSION: These observations support a possible role for catechol-o-methyltransferase polymorphism in the endocrine and subjective response to psychological stress and thus may qualify as a possible candidate gene involved in the pathogenesis of MDD.

Gender differences in the relation between social support, problems in parent-offspring communication, and depression and anxiety.

Gender differences in the buffer-effect of social support in the relation between stressful circumstances and the development of depression and anxiety disorders are widely assumed, but few studies address this three-way interaction between gender, stress, and support. Data in the present study came from the baseline assessment of the Adolescents at Risk for Anxiety and Depression (ARIADNE) study in 502 adolescent and young-adult children of 356 parents in the Netherlands with a depression, panic disorder and/or obsessive-compulsive disorder. Results indicate that the daughters benefit more from social support than the sons when problems in parent-offspring communication are high, but that this effect holds only for depression symptoms and particularly in relation to problems in father-offspring communication. Social support does not seem to play a role in the development of anxiety.

Future antidepressants: what is in the pipeline and what is missing?

Monoamine reuptake inhibitors still reign in the treatment of major depression, but possibly not for long. While medicinal chemists have been able to reduce the side effects of these drugs, their delayed onset of action and considerable non-response rate remain problematic. Of late, serious questions have been raised regarding the efficacy of monoamine reuptake inhibitors. The present review presents an inventory of what is (and until recently was) in the antidepressant pipeline of pharmaceutical companies. Novel antidepressant compounds can be categorised into four groups depending on their target(s): (i) monoamine receptors; (ii) non-monoamine receptors; (iii) neuropeptide receptors; and (iv) hormone receptors. Other possible targets include components of post-receptor intracellular processes and elements of the immune system; to date, however, compounds specifically aimed at these targets have not been the subject of clinical trials. Development of several compounds targeted at monoamine receptors has recently been discontinued. At least five neurokinin-1 (NK(1)) receptor antagonists were until recently in phase II of clinical testing. However, the apparent interest in the NK(1) receptor should not be interpreted as representing a departure from the monoamine hypothesis since neurokinins also modulate monoaminergic systems. In the authors' view, development of future antidepressants will continue to rely on the serendipity-based monoamine hypothesis. However, an alternative approach, based on the hypothesis that chronic stress precipitates depressive symptoms, might be more productive. Unfortunately, clinical results using drugs targeted at components of the HPA axis have not been very encouraging to date. In the short run, the authors believe that augmentation strategies offer the best hope for improving the efficacy of antidepressant treatment. Several approaches to improve the efficacy of SSRIs are conceivable, such as concurrent blockade of monoamine autoreceptors and the addition of antipsychotics, neuromodulators or hormones (HPA axis and gender related). In the long-term, however, construction of a scientifically verified conceptual framework will be needed before more effective antidepressants can be developed. It can be argued that it is not depression itself that should be treated, but rather that its duration should be reduced by pharmacological means. Animal models that take this concept into consideration and identify mechanisms for acceleration of recovery from the effects of stress need to be developed.

Acute cortisol effects on immediate free recall and recognition of nouns depend on stimulus valence.

The present study investigated the acute effects of cortisol administration in normal healthy male volunteers on immediate free recall and recognition of pleasant, unpleasant, and neutral nouns using a between-subjects double-blind design. Two hours after cortisol (10 mg) or placebo administration, impaired recall and recognition of neutral and pleasant words was found in the treatment group, whereas recall and recognition of unpleasant words was similar in both groups. The interaction between treatment and stimulus valence was not mediated by "semantic cohesion," nor does it seem to have been mediated by stimulus arousal. Cortisol did not change mood. The changes with cortisol in recall and recognition of pleasant and unpleasant words parallel those found in depression, a condition that is often accompanied by elevated basal cortisol levels.