Involvement In Depression Research Articles

Toward an Anti-Inflammatory Strategy for Depression

It has become clear that the inflammatory immune system is altered during the course of clinical depression. In particular, studies on human patients have found depression to be associated with disturbances in the trafficking of cells of the adaptive immune system, coupled with elevations of innate immune messengers and pro-inflammatory cytokines. Paralleling these findings, stressor-based animal models of depression have implicated several cytokines, most notably interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α. Elevations of these cytokines and general inflammatory indicators, such as C-reactive protein, together with reductions of specific immune cells (e.g., T lymphocytes) might serve as useful biomarkers of depression or at least, certain subtypes of the disorder. Recent reports also suggest the possibility that anti-inflammatory agents could have therapeutic value in acting as adjunct treatments with traditional anti-depressants. Along these lines, we presently discuss the evidence for pro-inflammatory cytokine involvement in depression, as well as the possibility that anti-inflammatory agents and trophic cytokines themselves might have important anti-depressant properties.

Variations in FKBP5 and BDNF genes are suggestively associated with depression in a Swedish population-based cohort

BackgroundGenetic variations in FKBP5, BDNF, P2RX7 and CACNA1 are current candidates for involvement in depression. MethodsThe single nucleotide polymorphisms FKBP5:rs1360780, BDNF:rs6265 (Val66Met), P2RX7:2230912 (Gln460Arg) and CACNA1C:rs1006737 were genotyped in DNA from 457 depression cases (major depression, dysthymia, and mixed anxiety depression) and 2286 healthy controls with no symptom of psychopathology. Cases and controls were derived from a large well-characterized longitudinal population-based sample of adult Swedes with data on life situation and life history. Association to depression was analyzed with and without consideration to problems during childhood and negative life events last year. ResultsFKBP5:rs1360780 allele T and genotype TT were overrepresented in depression for men. Childhood problems and negative life events (two or more) conferred a risk for depression (OR=2.8, 95% CI: 2.2–3.5 and OR=2.9, 95% CI: 2.4–3.7, respectively). The BDNF:rs6265 Met-allele was overrepresented in depression for women with problems during their childhood. No indication for association to depression was found for P2RX7:2230912 and CACNA1C:rs1006737 without or with consideration of childhood problems or negative life events. LimitationsThe sample size did not allow exclusion of true association to depression at low odds ratios. There was possibly some recall bias of childhood problems. ConclusionsThese data support previous reports on FKBP5:rs1360780 and show a gender difference. Likewise, they support previous reports on BDNF:rs6265 and show involvement of environmental stress. P2RX7:2230912 and CACNA1C:rs1006737 did not have a large or moderate-size effect on depression risk. Further studies are required to estimate the significance of these findings.

Extracellular levels of serotonin and GABA in the hippocampus after chronic mild stress in rats. A microdialysis study in an animal model of depression

One of the most established hypotheses of depression focuses on alteration of the serotonergic (5-HT) function. Recent evidence suggests that serotonergic involvement in depression may be modulated by the action of gamma-hydroxybutyric acid (GABA). Furthermore, altered GABAergic function is also evident in depressed patients and in animal models of depression. Disturbed sleep is characteristic of patients with mood disorders. The most pronounced changes of the 5-HT firing activity occur during sleep. Hence, the present paper reports a study on simultaneously measurement of hippocampal levels of serotonin and GABA during waking and sleep in the chronic mild stress (CMS) animal model of depression. The neurotransmitter findings are accompanied by depression-like symptoms (e.g. sleep alterations and reduced sucrose intake, a putative indicator of anhedonia in rodents). Our results show that animals exposed to CMS had lower hippocampal GABA levels compared to controls. In addition, after CMS there was a lack of 5-HT stage-dependency. A subgroup (five out of eight animals) showed a consistent increase in 5-HT levels in slow wave sleep and REM sleep. We also observed that this increase occurred in those animals regarded as most anhedonic (lowest intake of sucrose solution). Moreover, REM sleep was positively correlated with anhedonia. No interaction between 5-HT and GABA was found in the hippocampus. The data suggest that both GABAergic and serotonergic systems may be simultaneously but independently involved in depression. The alteration in 5-HT function may represent a link between depression-like behaviour and sleep abnormalities found in depressed patients.

Alteration of cardiac autonomic functions in patients with major depression: A study using heart rate variability measures

BackgroundDepression is associated with greater cardiac morbidity and mortality. One of the contributory factors for this may be altered cardiac autonomic activity in depression. However, cardiac autonomic involvement in depression remains controversial because of methodological issues. In this study, alteration of cardiac autonomic functions was studied in drug-naive patients with major depression without co-morbidity. Heart rate variability, a sensitive measure of neurocardiac autonomic regulation was used in addition to conventional methods of measuring cardiac autonomic functions. MethodsWe recruited 40 patients suffering from major depression, diagnosed based on DSM-IV-TR criteria. Their cardiac autonomic functions were measured using both conventional and heart rate variability measures. These were compared with those of age- and gender-matched healthy controls. ResultsPatients with major depression showed significantly lesser Valsalva ratio, maximum/minimum ratio and greater sympathovagal balance than healthy controls indicating decreased parasympathetic and increased sympathetic activity. ConclusionsDepression is associated with alteration of cardiac autonomic tone towards decreased parasympathetic activity and an increased sympathetic activity. It is possible that a common neurobiological dysfunction contributes to both depression and cardiac autonomic changes in the illness.

Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression

Abnormalities in L-glutamic acid (glutamate) and GABA signal transmission have been postulated to play a role in depression, but little is known about the underlying molecular determinants and neural mechanisms. Microarray analysis of specific areas of cerebral cortex from individuals who had suffered from major depressive disorder demonstrated significant down-regulation of SLC1A2 and SLC1A3, two key members of the glutamate/neutral amino acid transporter protein family, SLC1. Similarly, expression of L-glutamate-ammonia ligase, the enzyme that converts glutamate to nontoxic glutamine was significantly decreased. Together, these changes could elevate levels of extracellular glutamate considerably, which is potentially neurotoxic and can affect the efficiency of glutamate signaling. The astroglial distribution of the two glutamate transporters and L-glutamate-ammonia ligase strongly links glia to the pathophysiology of depression and challenges the conventional notion that depression is solely a neuronal disorder. The same cortical areas displayed concomitant up-regulation of several glutamate and GABA(A) receptor subunits, of which GABA(A)alpha1 and GABA(A)beta3 showed selectivity for individuals who had died by suicide, indicating their potential utility as biomarkers of suicidality. These findings point to previously undiscovered molecular underpinnings of the pathophysiology of major depression and offer potentially new pharmacological targets for treating depression.

Central GABAergic systems and depressive illness.

Clinical depression and other mood disorders are relatively common mental illnesses but therapy for a substantial number of patients is unsatisfactory. For many years clinicians and neuroscientists believed that the evidence pointed toward alterations in brain monoamine function as the underlying cause of depression. This point of view is still valid. Indeed, much of current drug therapy appears to be targeted at central monoamine function. Other results, though, indicate that GABAergic mechanisms also might play a role in depression. Such indications stem from both direct and indirect evidence. Direct evidence has been gathered in the clinic from brain scans or postmortem brain samples, and cerebrospinal fluid (CSF) and serum analysis in depressed patients. Indirect evidence comes from interaction of antidepressant drugs with GABAergic system as assessed by in vivo and in vitro studies in animals. Most of the data from direct and indirect studies are consistent with GABA involvement in depression.

Could Lack of Neuron Growth Factor Explain Why People Get Depressed?

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessCould Lack of Neuron Growth Factor Explain Why People Get Depressed?Joan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:15 Nov 2002https://doi.org/10.1176/pn.37.22.0018aIn 1986 an Italian scientist, Rita Levi-Montalcini, M.D., won a Nobel Prize in Medicine for the discovery of nerve growth factor. Since then, a number of factors have been found to influence the growth of neurons in the brain, and one of the most prevalent appears to be brain-derived neurotrophin factor.Lisa Monteggia, Ph.D., has made a notable advance in the neurotrophic growth factor arena that will likely benefit psychiatric illness research.Now a young American scientist—Lisa Monteggia, Ph.D., an assistant professor of psychiatry at the University of Texas Southwestern Medical Center at Dallas—and her colleagues appear to have made a notable advance in the neurotrophic growth factor arena. They have found a way to eliminate the gene for brain-derived neurotrophin factor from the brains of adult mice.Monteggia announced their achievement at the 14th Annual Scientific Symposium of the National Alliance for Research on Schizophrenia and Depression in New York City in October. She and her colleagues will soon be submitting a paper to a scientific journal describing the details of their technique.Now that Monteggia and her colleagues can knock out the gene for brain-derived neurotrophin factor, she explained at the symposium, they are going to use mice lacking this gene to explore the factor’s possible involvement in depression. For instance, they are going to see whether mice without the gene for the factor, and thus without the factor itself, appear to be depressed. If they are, it would suggest that lack of brain-derived neurotrophin factor, or at least an insufficient amount of it, might play a role in depression.In fact, there is already some evidence that an insufficient amount of the factor is involved in depression. For instance, antidepressant treatment has been found to increase the factor in the hippocampal region of the brain—a brain region increasingly implicated in depression (Psychiatric News, August 16).The ability of Monteggia and her team to eliminate the gene for brain-derived neurotrophic factor from the brains of adult mice appears to have wider implications. As Monteggia explained at the symposium, “This appears to be the first report of any system that can successfully knock out a gene in the brains of adult animals.”Lewis Judd, M.D., chair of psychiatry at the University of California at San Diego, not only agreed with her statement at the symposium, but amplified it: “This is really a stupendous piece of work technically. I can’t tell you how many people have tried to do such a thing but failed.”In fact, once genes implicated in various psychiatric disorders are identified, the system could probably be used to knock out those genes in adult mice, Monteggia told Psychiatric News. Then the mice could be used to study how those particular genes cause psychiatric illness. ▪ ISSUES NewArchived

Effects of bilateral olfactory bulbectomy on N-methyl-D-aspartate receptor function: autoradiographic and behavioral studies in the rat.

Rat bilateral olfactory bulbectomy (OBX) serves as a useful model in the study of depression and the mechanisms of action of antidepressant treatments. Considering the evidence of NMDA receptors involvement in depression, the present study was undertaken in order to investigate the time-course effects of OBX on the NMDA receptor function. Following bilateral olfactory bulbectomy, rats display an increase in locomotor activity and changes in other types of behavior in a novel environment. Autoradiographic experiments using the noncompetitive NMDA antagonist [(125)I]-iodo-MK-801 as the labeling agent showed that this increase in behavioral activities corresponds to a decrease in [(125)I]-iodo-MK-801 binding in a number of brain regions. In most regions, this reduction reached significance by the third week following OBX. However, in some cortical areas-a nucleus of the thalamus (AV) and one of the amygdala (LA)-this reduction was already significant in the first or second week following OBX and lasted throughout the 4 weeks of the study. We also compared the behavioral modifications induced by a challenge injection of MK-801 (0.2 mg/kg i.p.) in OBX and sham-operated rats. This challenge is known to induce hyperlocomotion and a number of stereotypies in naive rats. These effects were drastically reduced in OBX as compared to sham-operated rats. These data are consistent with the above-mentioned decrease in cerebral binding of MK-801 to NMDA receptors.

Depression and bipolar disorder: relationships to impaired fatty acid and phospholipid metabolism and to diabetes, cardiovascular disease, immunological abnormalities, cancer, ageing and osteoporosis Possible candidate genes

Depression and bipolar disorder are two of the commonest illnesses in the developed world. While some patients can be treated effectively with available drugs, many do not respond, especially in the depression related to bipolar disorder. Depression is associated with diabetes, cardiovascular disease, immunological abnormalities, multiple sclerosis, cancer, osteoporosis and ageing: in each case depressed individuals have a worse outcome than non-depressed individuals. In all of these conditions there is now evidence of impaired phospholipid metabolism and impaired fatty acid-related signal transduction processes. Impaired fatty acid and phospholipid metabolism may be a primary cause of depression in many patients and may explain the interactions with other diseases. Several novel gene candidates for involvement in depression and bipolar disorder are proposed.

Impaired specific cellular immunity to the varicella-zoster virus in patients with herpes zoster oticus.

The possible involvement of depression on cellular immunity in reactivation of varicella-zoster virus (VZV) in herpes zoster oticus was investigated. The subjects comprised 59 cases of herpes zoster oticus, 33 cases of herpes zoster sine herpete (ZSH) with facial paralysis, and 205 cases of Bell's palsy. The transformation rate of lymphocytes to phytohaemagglutinin in herpes zoster oticus tended to be lower than that in Bell's palsy. In skin tests with purified protein derivatives of tuberculin, the positivity rate in herpes zoster oticus was significantly lower than that in Bell's palsy (p < 0.015). In skin tests using VZV antigen the positivity rate in herpes zoster oticus and ZSH were significantly lower than that of Bell's palsy (p < 0.001 and p < 0.015, respectively). Thus, it was noted that cellular immunity, especially specific cellular immunity against VZV, was significantly depressed in herpes zoster oticus and ZSH. We consider that depression of specific cellular immunity plays an important role in triggering reactivation of VZV and onset of these diseases.

Frontal and parietal lobe dysfunction in depression: Delayed alternation and tactile learning deficits

To evaluate frontal and parietal lobe involvement in depression, behavioral tests sensitive to damage in these regions were administered to depressed patients over age 50. Delayed alternation (DA), delayed response and object alternation were used to assess dorsolateral frontal and orbitofrontal function. Tactile learning problems (TOL and TRL) assessed parietal lobe integrity. Depressed patients were significantly impaired on DA, TOL and TRL, suggesting spatial memory (DA) and tactile learning deficits. The functional neuroanatomy underlying these deficits may share features with Parkinson's and Alzheimer's diseases.

Genetic animal models of depression and ethanol preference provide support for cholinergic and serotonergic involvement in depression and alcoholism

The present article summarizes some comparative studies of the Fawn-Hooded (FH) rat, a potential animal model of ethanol preference, and the Flinders Sensitive Line (FSL) rat, a potential animal model of depression. Both FH and FSL rats exhibit high degrees of immobility in the forced swim test and have difficulty learning a two-way active avoidance task. However, there were no differences between the FH and FSL rats in the elevated plus maze. Studies of ethanol preference indicated high rates of ethanol intake (4g/kg) and preference (50%) in the FH rats, but low rates of ethanol intake (<1.1g/kg) and preference (<20%) in FSL rats. It is concluded that the FSL rats exhibit behaviors consistent with their being an animal model of depression, whereas the FH rats exhibit features consistent with their being an animal model of both depression and alcoholism. Psychopharmacological challenges indicated that both FSL and FH rats were more sensitive to the hypothermic effects of oxotremorine, a muscarinic agonist. However, FSL rats were also more sensitive to serotonergic agonists, and some of the present results and other investigators have reported serotonergic subsensitivity in the FH rats. Thus, FSL rats exhibit both cholinergic and serotonergic supersensitivity, whereas FH rats exhibit cholinergic supersensitivity but normal or reduced serotonergic sensitivity. Progeny from a genetic cross between FH and FSL rats exhibit cholinergic supersensitivity and have high ethanol preference scores. These data are consistent with genetic models suggesting that ethanol preference may be influenced by dominant genes, whereas cholinergic sensitivity may be influenced by recessive genes.

The Interactional Theory of Depression: A Meta-Analysis of the Research Literature

Coyne's (1976a) interactional theory of depression states that depressed people induce a negative mood in others through social interaction and hence elicit rejection from them. A meta-analysis was conducted to ssess the relationship between (1) depression and negative mood in others, (2) depression and rejection by others, and (3) negative mod and rejection by others. The results indicate strong support for the rejection component of the theory, but rather modest support for the negative mood induction hypothesis. Negative mood seems to show a curvilinear (inverted-U) relationship with depression

Right hemisphere involvement in depression: Toward a neuropsychological theory of negative affective experiences

Several lines of inquiry provide converging evidence for a critical role for the right cerebral hemisphere in negative affective experiences. This research includes the assessment of affective consequences of both focal cerebral lesions and pharmacological inactivation of one or the other hemisphere, as well as experimental and physiological techniques assessing differential hemispheric activation. The specific nature of right hemispheric involvement is conceptualized as a tendency to become activated by aversive experiences, and once activated, to process stimuli in a manner consistent with the right hemisphere's more negative affective tone. A theory of right hemisphere involvement in depressive affect is presented in detail and its relevance to clinical phenomena, e.g., the co-occurrence of depression and pain, and sex differences in depression, is examined, as is congruence with cognitive theories of depression.

The monoamine oxidase B inhibitor deprenyl potentiates phenylethylamine behaviour in rats without inhibition of catecholamine metabolite formation

The drug l-deprenyl has been reported to have antidepressant properties, and in the present study three possible mechanisms of action were investigated in animal experiments. l-Deprenyl, which is a type B monoamine oxidase (MAO) inhibitor, was compared to clorgyline, an MAO A inhibitor, with regard to its inhibitory effect on the formation of three major catecholamine metabolites, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylglycol (MOPEG) in the rat brain in vivo. Apart from a difference in dose levels the two drugs showed no difference in the dose-response pattern of all three metabolites. Clorgyline inhibited the formation of HVA, DOPAC and MOPEG With an ED 50 of about 0.2 mg/kg s.c. and l-deprenyl inhibited with an ED 50 of about 15 mg/kg s.c. This result strongly indicates that the metabolites of both dopamine and noradrenaline are formed by the same type of monoamine oxidase(s), probably type A, in the rat brain in vivo. Antidepressant properties of l-deprenyl therefore seem to be independent of catecholamine deamination. l-Deprenyl but not clorgyline (2 or 8 mg/kg s.c.) potentiated the stereotyped sniffing behaviour induced by β-phenylethylamine, a specific substrate for type B monoamine oxidase. This result is discussed in relation to a new hypothesis of phenylethylamine and dopamine involvement in depression. l-Deprenyl was 10,000 times less potent than DMI as inhibitor of noradrenaline uptake in crude synaptosomes from the occipital cortex of rat brain. Inhibition of noradrenaline uptake was therefore excluded as a possible mechanism for the antidepressant action of l-deprenyl.