The effect of supraphysiological dose of nandrolone decanoate administration on the inflammatory, neurotrophin and behavioral response in adult and old male mice.

This study examined the effect of 6 weeks of supraphysiological nandrolone decanoate (ND) administration in adult mice (7 months) on cognitive function and neuroinflammation during aging. Male C57BL/6 mice were randomized into ND (10 mg·kg-1·wk-1) or control (CTL) groups. Half of the mice were tested at a young (Y) age (ND-Y and CTL-Y), 1 week following final ND administration, while the remaining mice were tested at 16 months (O) (ND-O and CTL-O). Learning and memory were better in young mice compared to older mice, regardless of treatment. ND-O displayed decreased anxiety as compared to all other groups. TNFα and IL1ß expression were higher in older mice, regardless of treatment. ND administration in young mice appeared to attenuate the neuroinflammatory response in aging mice as evidenced by decreased COX2, IL-4 and increased IL-10 expression in ND-O compared to CTL-O. BDNF AR and ER expression increased in ND-O compared to CTL-O. Results of the study indicated that supraphysiological ND administration had no negative effect on learning and memory but may attenuate anxiety in older mice. In addition, ND administration in young adult mice may attenuate the inflammatory response during aging, which may be related to elevations in both AR and ER expression.

JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche.

Promoting adult hippocampal neurogenesis is expected to induce neuroplastic changes that improve mood and alleviate anxiety. However, the underlying mechanisms remain largely unknown and the hypothesis itself is controversial. Here we show that mice lacking Jnk1, or c-Jun N-terminal kinase (JNK) inhibitor-treated mice, display increased neurogenesis in adult hippocampus characterized by enhanced cell proliferation and survival, and increased maturation in the ventral region. Correspondingly, anxiety behaviour is reduced in a battery of tests, except when neurogenesis is prevented by AraC treatment. Using engineered retroviruses, we show that exclusive inhibition of JNK in adult-born granule cells alleviates anxiety and reduces depressive-like behaviour. These data validate the neurogenesis hypothesis of anxiety. Moreover, they establish a causal role for JNK in the hippocampal neurogenic niche and anxiety behaviour, and advocate targeting of JNK as an avenue for novel therapies against affective disorders.

JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche.

This corrects the article DOI: 10.1038/mp.2016.203.

Plant-derived flavanol (-)epicatechin mitigates anxiety in association with elevated hippocampal monoamine and BDNF levels, but does not influence pattern separation in mice.

Flavanols found in natural products such as cocoa and green tea elicit structural and biochemical changes in the hippocampus, a brain area important for mood and cognition. Here, we evaluated the outcome of daily consumption of the flavanol (-)epicatechin (4 mg per day in water) by adult male C57BL/6 mice on measures of anxiety in the elevated plus maze (EPM) and open field (OF). Furthermore, pattern separation, the ability to distinguish between closely spaced identical stimuli, considered to be mediated by the hippocampal dentate gyrus (DG), was tested using the touchscreen. To investigate mechanisms through which (-)epicatechin may exert its effects, mice were injected with bromodeoxyuridine (50 mg kg(-1)) to evaluate adult hippocampal neurogenesis. In addition, monoaminergic and neurotrophin signaling pathway proteins were measured in tissue derived from subject cortices and hippocampi. Flavanol consumption reduced anxiety in the OF and EPM. Elevated hippocampal and cortical tyrosine hydroxylase, downregulated cortical monoamine oxidase-A levels, as well as increased hippocampal brain-derived neurotrophic factor (BDNF) and pro-BDNF support the flavanol's anxiolytic effects. In addition, elevated pAkt in hippocampus and cortex was observed. (-)Epicatechin ingestion did not facilitate touchscreen performance or DG neurogenesis, suggesting a non-neurogenic mechanism. The concurrent modulation of complementary neurotrophic and monoaminergic signaling pathways may contribute to beneficial mood-modulating effects of this flavanol.

[Loss of sense and meaning, a neglected topic in psychiatry]. / Zinverlies; een verwaarloosd onderwerp in de psychiatrie.

Inherent in human existence is one's need to give sense to one's life. It is this need that drives life forward. In this paper the terms 'giving sense' and 'giving meaning' are used more or less interchangeably. A life acquires meaning when goals are set and attempts are made to achieve them. Giving meaning to one's existence often involves engaging in altruistic activity. The need to give sense to one's life can be felt to be 'self generated' or metaphysically inspired, in other words inspired by a supernatural authority. Sense-deficiency is a mental condition which is barely recognised in psychiatry and hardly ever treated. Thorough research is needed to find the causes and the appropriate treatment and, in particular, to discover to what extent the spiritual domain is able to perform therapeutic functions. A discussion of certain aspects of this domain should be given a definitive place in the curriculum of trainee psychiatrists.

Stress and suicide are we well-equipped to study this issue?

Stress almost always precedes suicidality. Stress also is a harbinger of a variety of psychiatric disorders, most notably depression. Depression is a major precursor of suicidal behavior. Consequently, the question of whether stress is an epiphenomenon or a decisive factor in the causation of suicidality and (certain forms of) mood disorders is crucial. Certainty about this question can only be obtained when it can be demonstrated that stress phenomena may induce changes in brain functioning similar to the ones supposedly associated with suicidality and with (certain forms of) depression. Since the phenomenology of stress syndromes, as well as their emotional intensity, are highly variable, careful definition of the stress syndrome to be studied is a first requirement. In studies into the significance of stress in the occurrence of suicidality and depression, this degree of finesse has not been achieved. The major shortcomings have been discussed. These should be systematically addressed to provide research into the relation between stress and psychopathology with the necessary acuity.

The cognitive paradox in posttraumatic stress disorder: a hypothesis.

Posttraumatic stress disorder (PTSD) is characterized by a peculiar cognitive state. The traumatic event(s) are partly hypermemorized, partly blurred, whereas the ability to store and retrieve new information is impaired. The question is raised as to what the biological systems might be that 'carry' this cognitive paradox. Four possible candidate systems are discussed. It is concluded that understimulation of the corticosteroid receptors, particularly the glucocorticoid receptors (GRs), overactivity of the noradrenaline (NA) and vasopressin (VA) systems, and deficits in the 5-Hydroxytryptamine (5-HT) system, particularly the 5-HT(1A) system, could generate a cognitive syndrome similar to the one observed in PTSD. A dual hypothesis is launched holding that (a) in PTSD, downregulation of the 5-HT(1A) receptor system is the primary lesion, while the other dysfunctions mentioned are subsidiaries and that (b) underdevelopment of or damage to the 5-HT(1A) receptor system will make a person PTSD-prone.

Can stress cause depression?

The central issue raised in this paper is: can stress cause depression? Phrased more precisely: can stress cause brain disturbances thought to underlie (certain forms of) depression or particular components of the depressive syndrome. Focussing on 5-hydroxytryptamine (5-HT) and the stress hormones, this question was answered in the affirmative, based on the following two considerations: changes in the 5-HT and stress hormone systems produced by sustained stress mimic to a substantial extent the disturbances in these systems that may be observed in depression. Substantial evidence indicates that the 5-HT and stress hormone disturbances in depression are of pathophysiological significance and not merely a consequence of the depressed state or a product of stress generated by the depressed state. Furthermore, the question was raised whether a depression type could be identified particularly stress-inducible. This question, too, was answered in the affirmative. The depression type in question was named anxiety/aggression-driven depression and characterized on three levels: psychopathologically, biologically and psychologically. Preferential treatment of this depression type was discussed. In studying stress-inducible depression, biological depression research should shift focus from depression per se to the neurobiological sequelae of stress. Treatment of stress-inducible depressions and particularly its prevention should be geared towards reduction of stress and stress sensitiveness, utilising both biological and psychological means.

Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo.

We have previously shown that voluntary exercise produces enhanced neurogenesis and long-term potentiation (LTP) in the dentate gyrus (DG) of mice in vitro. In the present experiments we show that rats given access to a running wheel (Runners) exhibit significantly more short-term potentiation and LTP with theta-patterned conditioning stimulation in vivo than do age-matched litter mates (Controls). This increase in LTP appears to reflect an alteration in the induction threshold for synaptic plasticity that accompanies voluntary exercise. Weak theta-patterned stimulation, which did not produce LTP in control subjects, produced a robust and long-lasting LTP in Runners. LTP induction in both groups was dependent upon the activation of N-methyl-D-aspartate (NMDA) receptors, and could be blocked by the competitive antagonist [+/-]-3-[2-carboxypiperazin-4-yl] propanephosphonic acid. Consistent with these findings, we found that mRNA levels for NR2B subtype of NMDA receptor were increased specifically in the DG of Runners. In addition to changes in NR2B mRNA levels, quantitative polymerase chain reaction analysis revealed that brain-derived neurotrophic factor (BDNF) and glutamate receptor 5 mRNA levels were also significantly elevated in the DG of Runners, but not in other areas of the hippocampus. Thus, alterations in the expression of BDNF, and specific glutamate receptor subtypes, may underlie the ability of exercise to enhance neurogenesis and reduce the threshold for LTP in the DG.

Itinerary: Concerning the professional and spiritual objectives of my life.

In this paper I look back on my life, on what have I tried to achieve professionally, and on what trends and theories I have opposed. Next I discuss the convictions and considerations that constituted the building blocks for the spiritual foundation of my life. I reach the conclusion that the building blocks were derived from Judaism and explain why that is so. Finally, I conclude that the scientific and the theological ingredients of my life relate reciprocally and do not exist independently.

Cardiological risk factors for depressive symptoms after a first myocardial infarction.

OBJECTIVE: To detect possible cardiological risk factors in the acute phase of MI for developing depressive symptoms after first MI. DESIGN: Retrospective analysis of cardiac and psychiatric data of 111 consecutive patients admitted with a first MI. METHODS: During one year, all consecutive patients with a first MI, less than 12 hours chest pain and a maximal aspartate aminotransferase (ASAT) value of at least 80 U/l, admitted to the University Hospital of Maastricht, were screened for the presence of depressive symptoms using the 90-item 'Symptom checklist' (SCL-90) questionnaire at one month post-MI. Inclusion criteria were fulfilled by 111 patients; 28 patients refused to participate in the study. RESULTS: No correlation was found between LVEF, peak ASAT, peak CK value and characteristics, location or mode of treatment of the MI and depressive symptoms post-MI. A statistically significant negative correlation was found between SCL-90 depression score and cardiac tissue loss as defined by cumulative ASAT release at 24, 48 and 72 hours after the acute event (p values 0.029, 0.028 and <0.009, respectively) at the one month post-MI screening. CONCLUSIONS: No cardiological parameters were correlated to depressive symptoms post-MI. If there was a connection at all, this appeared to be a negative correlation between infarct size as measured by ASAT release and the occurrence of depressive symptoms at one month post-MI.

Why has the antidepressant era not shown a significant drop in suicide rates?

Over the past decades the rate of completed suicide has remained quite stable, whereas that of suicide attempts seems to have increased (to the extent it has been studied in defined regions). These are puzzling observations, since depression is the major suicide precursor and and since antidepressants have been increasingly used over the years in the treatment of depression. These observations have not attracted sufficient attention, possibly because they do not accord with consensus opinions about depression treatment in psychiatry today. This paper discusses a number of possible explanations that not only deserve, but are definitely in need of systematic investigation.

Mood congruent memory bias induced by tryptophan depletion.

BACKGROUND: Mood congruent memory bias predicts a more superior recall memory of learnt material congruent with the mood state at the time of learning. The present study is the first report of an experimental study in which a biological mood induction was used to test this hypothesis. The influence of acute tryptophan (TRP) depletion, inducing low serotonin neurotransmission and a depression of mood, on memory bias was evaluated in healthy volunteers (16 with and 11 without a family history of major affective disorder). METHODS: Twenty-seven subjects received 100 g of an amino acid mixture with and without TRP according to a placebo-controlled, double-blind, balanced, cross-over design. An affective memory test consisting of a 30-word list with words of positive, neutral, and negative affective valence and a mood questionnaire were assessed at 6 and 24 h following treatment administration. RESULTS: TRP depletion impaired delayed recall of neutral and positive words, but not of negative words. There was no interaction of family history and treatment and there was no post hoc association between the influence of TRP-depletion on mood and on affective memory bias. CONCLUSION: Experimentally induced serotonergic depletion in normal individuals shifts affective memory bias towards negative affective valent verbal stimuli.

Dissociable hormonal, cognitive and mood responses to neuroendocrine challenge: evidence for receptor-specific serotonergic dysregulation in depressed mood.

Fifteen patients with major depression, dysthymia, or anxiety disorder with depressed mood (DSM-IV diagnoses) and 16 controls received single oral doses of 0.5mg/kg metachlorophenylpiperazine (m-CPP), a 5-HT(2C) agonist, and 10 mg ipsapirone, a 5-HT(1A) agonist, according to double-blind, placebo-controlled, cross-over design. The groups' levels of cortisol, adrenocorticotrophic hormone (ACTH) and prolactin did not differ at baseline. Both 5-HT agonists significantly elevated cortisol, ACTH, and prolactin. The cortisol response to ipsapirone was significantly blunted in major depression and dysthymia patients. Neuroendocrine responses to m-CPP did not differ between groups, but m-CPP selectively increased profile of mood states (POMS) depression and tenseness scores in patients. No effects of ipsapirone on mood were found. However, ipsapirone impaired memory performance in controls, but tended to improve memory performance in patients. The results support the evidence for both hypothalamic and possibly hippocampal 5-HT(1A) receptor desensitisation and non-hypothalamic, 5-HT(2C) receptor sensitisation, probably fronto-cortical, in patients with major depression and dysthymia.

Crossroads of corticotropin releasing hormone, corticosteroids and monoamines. About a biological interface between stress and depression.

Mental disorders are frequently preceded by stressful events or situations. Depression is a typical case in point. This raises the question, is depression - or possibly better: are certain forms of depression - caused by stress? Can stress be a true pathogenic factor? Phrased differently: can stress destabilize neuronal systems in the central nervous system to such an extent that depressive symptoms are generated? This question is discussed with the corticotrophin releasing hormone (CRH) and MA systems and hypothalamic-pituitary-adrenal (HPA) axis as major foci. The following issues are explored: the effect of antidepressants on corticosteroid receptor gene expression; the behavioral sequellae of CRH administration; CRH disturbances in depression; the impact of early life adversity on the development of the CRH system and on stress reactivity; the interrelationships of stress hormones and monoaminergic (MA ergic) transmission and finally the therapeutic potential of CRH and cortisol antagonists. The available data suggest that CRH overdrive and cortisol overproduction may play a pathogenic role in the occurrence of certain types of depression, directly and/or indirectly, i.e. by induction or exacerbation of disturbances in MA ergic transmission. Stress should, thus, become a major focus of biological depression research.

Anxiety/aggression--driven depression. A paradigm of functionalization and verticalization of psychiatric diagnosis.

A new subtype of depression is proposed, named: anxiety/aggression-driven depression. The psychopathological, psychopharmacological and biochemical evidence on which this construct is based, is being discussed. Selective postsynaptic 5-HT1A agonists together with CRH and/or cortisol antagonists are hypothesized to be a specific biological treatment for this depression type, in conjunction with psychological interventions to raise the stressor-threshold and to increase coping skills. The development of this depression construct has been contingent on the introduction of two new diagnostic procedures, called functionalization and verticalization of psychiatric diagnosis. These procedures are explained and it is stressed that they are essential to psychiatric diagnosing, in order to put this process on a scientific footing.