ABSTRACT
OBJECTIVE: The role of baseline severity as effect modifier in various psychiatric disorders is a topic of controversy and of clinical import. This study aims to examine whether baseline severity modifies the efficacy of various antidepressants for major depression through individual participant data (IPD) meta-analysis. METHOD: We identified all placebo-controlled, double-blind randomised trials of new generation antidepressants in the acute phase treatment of major depression conducted in Japan and requested their IPD through the public-private partnerships (PPPs) between the relevant academic societies and the pharmaceutical companies. The effect modification by baseline depression severity was examined through six increasingly complex competing mixed-effects models for repeated measures. RESULTS: We identified eleven eligible trials and obtained IPD from six, which compared duloxetine, escitalopram, mirtazapine, paroxetine or bupropion against placebo (total n = 2464). The best-fitting model revealed that the interaction between baseline severity and treatment was not statistically significant (coefficient = -0.04, 95% confidence interval: -0.16 to 0.08, P = 0.49). Several sensitivity analyses confirmed the robustness of the findings. CONCLUSION: We may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression. Clinical practice guidelines will need to take these findings into consideration.
Subject(s)
Antidepressive Agents, Second-Generation/pharmacology , Depressive Disorder, Major/drug therapy , Outcome Assessment, Health Care/statistics & numerical data , Severity of Illness Index , Adult , Aged , Humans , Middle Aged , Young AdultABSTRACT
BACKGROUND: Cognitive-behavioral therapy (CBT) is thought to be useful for chronic pain, with the pathology of the latter being closely associated with cognitive-emotional components. However, there are few resting-state functional magnetic resonance imaging (R-fMRI) studies. We used the independent component analysis method to examine neural changes after CBT and to assess whether brain regions predict treatment response. METHODS: We performed R-fMRI on a group of 29 chronic pain (somatoform pain disorder) patients and 30 age-matched healthy controls (T1). Patients were enrolled in a weekly 12-session group CBT (T2). We assessed selected regions of interest that exhibited differences in intrinsic connectivity network (ICN) connectivity strength between the patients and controls at T1, and compared T1 and T2. We also examined the correlations between treatment effects and rs-fMRI data. RESULTS: Abnormal ICN connectivity of the orbitofrontal cortex (OFC) and inferior parietal lobule within the dorsal attention network (DAN) and of the paracentral lobule within the sensorimotor network in patients with chronic pain normalized after CBT. Higher ICN connectivity strength in the OFC indicated greater improvements in pain intensity. Furthermore, ICN connectivity strength in the dorsal posterior cingulate cortex (PCC) within the DAN at T1 was negatively correlated with CBT-related clinical improvements. CONCLUSIONS: We conclude that the OFC is crucial for CBT-related improvement of pain intensity, and that the dorsal PCC activation at pretreatment also plays an important role in improvement of clinical symptoms via CBT.
Subject(s)
Chronic Pain/therapy , Cognitive Behavioral Therapy , Gyrus Cinguli/physiopathology , Magnetic Resonance Imaging , Prefrontal Cortex/physiopathology , Adult , Brain Mapping , Case-Control Studies , Chronic Pain/physiopathology , Female , Humans , Japan , Male , Middle Aged , Neural Pathways/physiopathology , Psychotherapy, Group , Rest , Spatial RegressionABSTRACT
Stress-related psychopathology is highly prevalent among elderly individuals and is associated with detrimental effects on mood, appetite and cognition. Conversely, under certain circumstances repeated mild-to-moderate stressors have been shown to enhance cognitive performance in rodents and exert stress-inoculating effects in humans. As most stress-related favorable outcomes have been reported in adolescence and young-adulthood, this apparent disparity could result from fundamental differences in how aging organisms respond to stress. Furthermore, given prominent age-related alterations in sex hormones, the effect of chronic stress in aging females remains a highly relevant yet little studied issue. In the present study, female C57BL/6 mice aged 3 (young-adult) and 20-23 (old) months were subjected to 8 weeks of chronic unpredictable stress (CUS). Behavioral outcomes were measured during the last 3 weeks of the CUS protocol, followed by brain dissection for histological and molecular end points. We found that in young-adult female mice, CUS resulted in decreased anxiety-like behavior and enhanced cognitive performance, whereas in old female mice it led to weight loss, dysregulated locomotion and memory impairment. These phenotypes were paralleled by differential changes in the expression of hypothalamic insulin and melanocortin-4 receptors and were consistent with an age-dependent reduction in the dynamic range of stress-related changes in the hippocampal transcriptome. Supported by an integrated microRNA (miRNA)-mRNA expression analysis, the present study proposes that, when confronted with ongoing stress, neuroprotective mechanisms involving the upregulation of neurogenesis, Wnt signaling and miR-375 can be harnessed more effectively during young-adulthood. Conversely, we suggest that aging alters the pattern of immune activation elicited by stress. Ultimately, interventions that modulate these processes could reduce the burden of stress-related psychopathology in late life.
Subject(s)
Anxiety/metabolism , Cognition/physiology , Stress, Psychological/metabolism , Age Factors , Animals , Behavior, Animal , Brain/metabolism , Female , Hippocampus/metabolism , Mice , Mice, Inbred C57BL , Neurobiology , Neurogenesis/physiologyABSTRACT
BACKGROUND: It has been demonstrated that negatively distorted self-referential processing, in which individuals evaluate one's own self, is a pathogenic mechanism in subthreshold depression that has a considerable impact on the quality of life and carries an elevated risk of developing major depression. Behavioural activation (BA) is an effective intervention for depression, including subthreshold depression. However, brain mechanisms underlying BA are not fully understood. We sought to examine the effect of BA on neural activation during other perspective self-referential processing in subthreshold depression. METHOD: A total of 56 subjects underwent functional magnetic resonance imaging scans during a self-referential task with two viewpoints (self/other) and two emotional valences (positive/negative) on two occasions. Between scans, while the intervention group (n = 27) received BA therapy, the control group (n = 29) did not. RESULTS: The intervention group showed improvement in depressive symptoms, increased activation in the dorsal medial prefrontal cortex (dmPFC), and increased reaction times during other perspective self-referential processing for positive words after the intervention. Also, there was a positive correlation between increased activation in the dmPFC and improvement of depressive symptoms. Additionally, there was a positive correlation between improvement of depressive symptoms and increased reaction times. CONCLUSIONS: BA increased dmPFC activation during other perspective self-referential processing with improvement of depressive symptoms and increased reaction times which were associated with improvement of self-monitoring function. Our results suggest that BA improved depressive symptoms and objective monitoring function for subthreshold depression.
Subject(s)
Behavior Therapy/methods , Depression/physiopathology , Depression/therapy , Outcome Assessment, Health Care , Prefrontal Cortex/physiopathology , Self Concept , Self-Control , Adolescent , Adult , Depression/diagnostic imaging , Female , Humans , Magnetic Resonance Imaging , Male , Prefrontal Cortex/diagnostic imaging , Young AdultABSTRACT
Despite novel antidepressant development, 10-30% of patients with major depressive disorder (MDD) have antidepressant treatment-resistant depression (TRD). Although new therapies are needed, lack of knowledge regarding the neural mechanisms underlying TRD hinders development of new therapeutic options. We aimed to identify brain regions in which spontaneous neural activity is not only altered in TRD but also associated with early treatment resistance in MDD. Sixteen patients with TRD, 16 patients with early-phase non-TRD and 26 healthy control (HC) subjects underwent resting-state functional magnetic resonance imaging. To identify brain region differences in spontaneous neural activity between patients with and without TRD, we assessed fractional amplitude of low-frequency fluctuations (fALFF). We also calculated correlations between the percent change in the Hamilton Rating Scale for Depression (HRSD17) scores and fALFF values in brain regions with differing activity for patients with and without TRD. Patients with TRD had increased right-thalamic fALFF values compared with patients without TRD. The percent change in HRSD17 scores negatively correlated with fALFF values in patients with non-TRD. In addition, patients with TRD showed increased fALFF values in the right inferior frontal gyrus (IFG), inferior parietal lobule (IPL) and vermis, compared with patients with non-TRD and HC subjects. Our results show that spontaneous activity in the right thalamus correlates with antidepressant treatment response. We also demonstrate that spontaneous activity in the right IFG, IPL and vermis may be specifically implicated in the neural pathophysiology of TRD.
Subject(s)
Depressive Disorder, Major/diagnostic imaging , Depressive Disorder, Treatment-Resistant/diagnostic imaging , Parietal Lobe/diagnostic imaging , Prefrontal Cortex/diagnostic imaging , Thalamus/diagnostic imaging , Adult , Antidepressive Agents/therapeutic use , Brain/diagnostic imaging , Brain/physiopathology , Case-Control Studies , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/physiopathology , Depressive Disorder, Treatment-Resistant/drug therapy , Depressive Disorder, Treatment-Resistant/physiopathology , Female , Functional Neuroimaging , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Parietal Lobe/physiopathology , Prefrontal Cortex/physiopathology , Thalamus/physiopathologyABSTRACT
OBJECTIVE: Many studies have examined the effects of cerebrovascular changes on treatment response in geriatric depression. However, few such studies have examined the relationship between cerebrovascular changes and long-term prognosis. We examined the effects of cerebrovascular changes on the course of geriatric depressive symptoms, dementia rates, and mortality over a follow-up period of approximately 10 years. METHOD: Participants were 84 patients with major depression (age of onset over 50 years); patients suffering from strokes, neurological disorders, and other psychiatric disorders were excluded. Magnetic resonance imaging findings were used to classify all patients into silent cerebral infarction (SCI)-positive (n = 37) or SCI-negative groups (n = 47). Prognoses were ascertained using a review of clinical charts and mailed questionnaires. RESULTS: Only 5% of patients with SCI were able to maintain remission whereas 36% of patients without SCI were able to do so. Total duration of depressive episodes was significantly longer in the SCI-positive group than in the SCI-negative group. SCI was also associated with a higher risk of dementia. CONCLUSION: The results of this long-term follow-up study demonstrate that the presence of SCI is associated with a relatively poor prognosis in geriatric depression.
Subject(s)
Cerebral Infarction/diagnosis , Depressive Disorder, Major/diagnosis , Geriatric Assessment/statistics & numerical data , Aged , Cerebral Infarction/complications , Cerebral Infarction/mortality , Dementia/complications , Depressive Disorder, Major/complications , Depressive Disorder, Major/mortality , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Prognosis , Risk FactorsABSTRACT
It is well known that early life events induce long-lasting psychophysiological and psychobiological influences in later life. In rodent studies, environmental enrichment after weaning prevents the adulthood behavioral and emotional disturbances in response to early adversities. We compared the behavioral effect of neonatal isolation (NI) with the effect of NI accompanied by tactile stimulation (NTS) to determine whether NTS could reverse or prevent the effects of NI on the adulthood behavioral and emotional responses to environmental stimuli. In addition, we also examined the sex difference of the NTS effect. Measurements of body weights, an open-field locomotor test, an elevated plus maze test, a hot-plate test, and a contextual fear-conditioning test were performed on postnatal day 60. As compared with rats subjected to NI, rats subjected to NTS showed significantly higher activity and exploration in the open-field locomotor test, lower anxiety-like behavior in the elevated plus maze test, and significantly prolonged latencies in the hot-plate test, and this effect was equal among males and females. In the contextual fear-conditioning test, whereas NTS significantly reduced the enhanced freezing time due to NI in females, no significant difference in the freezing time between NI and NTS was found in males. These findings indicate that adequate tactile stimulation in early life plays an important role in the prevention of disturbances in the behavioral and emotional responses to environmental stimuli in adulthood induced by early adverse experiences.
Subject(s)
Animals, Newborn/physiology , Anxiety/psychology , Pain Threshold/psychology , Social Isolation/psychology , Touch/physiology , Analysis of Variance , Animals , Animals, Newborn/psychology , Anxiety/etiology , Conditioning, Classical/physiology , Environment , Exploratory Behavior/physiology , Female , Male , Pain Threshold/physiology , Rats , Rats, Sprague-Dawley , Sex Factors , Statistics, NonparametricABSTRACT
The aging behavior of polymer glass, poly(methyl methacrylate), has been investigated through the measurement of the ac-dielectric susceptibility at a fixed frequency after a temperature shift deltaT (< or = 20 K) between two temperatures T1 and T2. A crossover from cumulative aging to noncumulative aging could be observed with increasing deltaT using a twin-temperature (T-) shift measurement. Based on the growth law of a dynamical coherent length given by activated dynamics, we obtain a unique coherent length for positive and negative T shifts. The possibility of the existence of temperature chaos in polymer glasses is discussed.
ABSTRACT
Critical to our many daily choices between larger delayed rewards, and smaller more immediate rewards, are the shape and the steepness of the function that discounts rewards with time. Although research in artificial intelligence favors exponential discounting in uncertain environments, studies with humans and animals have consistently shown hyperbolic discounting. We investigated how humans perform in a reward decision task with temporal constraints, in which each choice affects the time remaining for later trials, and in which the delays vary at each trial. We demonstrated that most of our subjects adopted exponential discounting in this experiment. Further, we confirmed analytically that exponential discounting, with a decay rate comparable to that used by our subjects, maximized the total reward gain in our task. Our results suggest that the particular shape and steepness of temporal discounting is determined by the task that the subject is facing, and question the notion of hyperbolic reward discounting as a universal principle.
Subject(s)
Choice Behavior/physiology , Decision Making/physiology , Game Theory , Models, Biological , Reward , Task Performance and Analysis , Adaptation, Physiological/physiology , Computer Simulation , Computer Systems , Humans , Time FactorsABSTRACT
Previous studies suggested that omega-3 fatty acids (FAs) have therapeutic effects against depression, but there is no evidence in the oncological setting. Our preliminary study reported the association between lower omega-3 FA intake and occurrence of depression in lung cancer patients. To explore the association further, the present study examined whether depression was associated with lower levels of omega-3 FAs in serum phospholipids. A total of 717 subjects in the Lung Cancer Database Project were divided into three groups by two cutoff points of the Hospital Anxiety and Depression Scale depression subscale (HADS-D). In all, 81 subjects of the nondepression and minor depression groups (HADS-D<5 and 5
Subject(s)
Depressive Disorder/etiology , Fatty Acids, Omega-3/blood , Lung Neoplasms/pathology , Lung Neoplasms/psychology , Aged , Case-Control Studies , Depressive Disorder/physiopathology , Female , Humans , Male , Middle Aged , Severity of Illness IndexABSTRACT
Various neurobiological studies of aging indicate that elevated levels of circulating glucocorticoids lead to hippocampal vulnerability to stress, though little is known about the molecular mechanism underlying stress vulnerability in the elderly. We have compared the gene expression profiles in the hippocampus of aged (20 months) and adult (3 months) rats in response to repeated variable stress (RVS) for 4 days, using a cDNA array technique and real-time quantitative PCR, to identify putative genes involved in the mechanism of stress vulnerability in the elderly. We found a significant decrease in the levels of amphiphysin 1 mRNA in aged rats subjected to RVS compared with treated and untreated adult rats or to untreated aged rats. Similarly, we found a significant decrease in hippocampal levels of amphiphysin 1 mRNA in aged rats subjected to RVS for 8 days, but not in those subjected to a single VS. These findings suggest that the decrease in the hippocampal levels of amphiphysin 1 mRNA in response to repeated stress may be involved in the stress vulnerability in the elderly, and may lead to the disturbance of learning and memory under stressful conditions in the elderly.
Subject(s)
Aging/metabolism , Hippocampus/metabolism , Nerve Tissue Proteins/biosynthesis , RNA, Messenger/biosynthesis , Stress, Physiological/metabolism , Aging/genetics , Animals , Gene Expression Profiling/methods , Male , Nerve Tissue Proteins/genetics , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley , Stress, Physiological/geneticsABSTRACT
To clarify the mechanism of adaptation to stress in the brain, we performed neuroimaging studies by functional magnetic resonance imaging and magnetoencephalography. First, to investigate which areas of the brain play an important role in the perception of stressful events, we performed fMRI for recognition of unpleasant words concerning interpersonal relationships. Secondly, we evaluated the effect of various stresses on the sensory gating system by MEG to show whether stress could affect the brain mechanism. Finally, we studied the neural activity associated with the expectancy of emotional stimuli using fMRI and MEG, because of the importance of expectancy in adaptation to stress. Our results suggested that stressful events might be recognized in the same brain regions, that acute stress might affect one brain mechanism, and that expectancy might suppress incoming stressful stimuli.
Subject(s)
Adaptation, Physiological , Brain/physiology , Stress, Psychological , Brain/pathology , Brain/physiopathology , Humans , Interpersonal Relations , Language , Magnetic Resonance Imaging , MagnetoencephalographyABSTRACT
Protein phosphatase 2A (PP2A) regulates protein kinase cascades and thus plays an important role in the regulation of cell growth, gene expression and development. We examined the influence of lithium and valproate on the expression of PP2A and its serine/threonine phosphatase activity in the rat frontal cortex and hippocampus. Western blot and immunohistochemical analyses demonstrated that neither lithium nor valproate treatment had an effect on the levels of PP2A immunoreactivity in these brain regions. However, administration of lithium for 1 or 14 days significantly upregulated the activity of PP2A in the frontal cortex. Similarly, lithium administration tended to increase the activity of PP2A in the hippocampus. In contrast, neither a single nor repeated administration of valproate affected the activity of PP2A in these brain regions. These findings indicate that lithium, but not valproate, upregulated the activity of PP2A in the rat brain. It is suggested that the changes in neuronal functions induced by PP2A may be, at least in part, associated with the therapeutic action of lithium.
Subject(s)
Brain/drug effects , Lithium Chloride/pharmacology , Phosphoprotein Phosphatases/metabolism , Valproic Acid/pharmacology , Animals , Brain/enzymology , Enzyme Activation/drug effects , Enzyme Induction/drug effects , Enzyme Induction/physiology , Gene Expression Regulation, Enzymologic/drug effects , Male , Phosphoprotein Phosphatases/biosynthesis , Protein Phosphatase 2 , Rats , Rats, Sprague-DawleyABSTRACT
Functional neuroimaging studies on patients with depression have found abnormal activity in the left prefrontal and anterior cingulate cortex compared with healthy controls. Other studies have shown that these regions become active in healthy subjects during verbal fluency tasks, while patients with depression show impaired performance on such tasks. We used functional magnetic resonance imaging to investigate changes in cerebral blood oxygenation associated with a verbal fluency task in depressed patients and healthy volunteers. In contrast to 10 age- and sex-matched healthy control subjects who activated the left prefrontal cortex and the anterior cingulate cortex during word generation, 10 depressed subjects showed attenuated activation in the left prefrontal cortex and did not show significant activation in the anterior cingulate cortex. These findings suggest that impaired performance during verbal fluency task in depressed patients is associated with abnormal neural responses within these regions.
Subject(s)
Depressive Disorder, Major/physiopathology , Prefrontal Cortex/physiopathology , Verbal Behavior , Brain Mapping , Case-Control Studies , Depressive Disorder, Major/psychology , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Neuropsychological Tests , Task Performance and AnalysisABSTRACT
We report a case of Meige syndrome with apraxia of lid opening that lasted for about seven months after discontinuation of sulpiride treatment. To our knowledge, this is the first report demonstrating that Meige syndrome with apraxia of lid opening is induced by sulpiride, and that the condition persists.
Subject(s)
Antidepressive Agents, Second-Generation/adverse effects , Apraxias/chemically induced , Dopamine Antagonists/adverse effects , Eyelid Diseases/chemically induced , Meige Syndrome/chemically induced , Sulpiride/adverse effects , Adult , Female , HumansABSTRACT
To investigate the clinical significance of circulating angiogenic factors, especially in association with early relapse of osteosarcoma, we quantified pre-therapeutic levels of vascular endothelial growth factor, basic fibroblast growth factor and placenta growth factor in the sera of 16 patients with osteosarcoma using an enzyme-linked immunosorbent assay. After a 1-year follow-up, the serum level of angiogenic factors was analysed with respect to microvessel density of the biopsy specimen and clinical disease relapse. The serum vascular endothelial growth factor levels were positively correlated with the microvessel density with statistical significance (P=0.004; Spearman rank correlation) and also significantly higher in seven patients who developed pulmonary metastasis than the remaining nine patients without detectable disease relapse (P=0.0009; The Mann-Whitney U-test). In contrast, the serum levels of basic fibroblast growth factor or placenta growth factor failed to show significant correlation with the microvessel density or relapse of the disease. Although there was no significant correlation between serum vascular endothelial growth factor levels and the tumour volume, the serum vascular endothelial growth factor levels were significantly higher in patients with a vascular endothelial growth factor-positive tumour than those with a vascular endothelial growth factor-negative tumour. These findings suggest that the pre-therapeutic serum vascular endothelial growth factor level reflects the angiogenic property of primary tumour and may have a predictive value on early disease relapse of osteosarcoma.
Subject(s)
Bone Neoplasms/blood , Endothelial Growth Factors/blood , Lymphokines/blood , Osteosarcoma/blood , Adult , Aged , Bone Neoplasms/blood supply , Bone Neoplasms/pathology , Endothelial Growth Factors/analysis , Female , Fibroblast Growth Factor 2/blood , Humans , Lung Neoplasms/secondary , Lymphokines/analysis , Male , Middle Aged , Osteosarcoma/blood supply , Osteosarcoma/pathology , Placenta Growth Factor , Pregnancy Proteins/blood , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
In this study, we characterized cognitive functioning in patients with major depression and silent cerebral infarction (SCI), as detected by magnetic resonance imaging (MRI), after they had recovered from depression. Thirty-five patients with unipolar depression who experienced the onset of depression after the age of 50 underwent MRI and were classified as SCI(+) (n = 17) or SCI(-) (n = 18). The Wechsler Adult Intelligence Scale-Revised (WAIS-R) and the Uchida-Kraepelin psychodiagnostic test were administered after the patients had recovered from depression. In addition, the intelligence quotient (IQ) and mental speed of the patients in the two groups were compared. The total, verbal and performance IQ scores, as determined by the WAIS-R, were significantly lower in the SCI(+) group than in the SCI(-) group. The mental speed of patients in the SCI(+) group, as assessed by the Uchida-Kraepelin psychodiagnostic test, was almost half that of the SCI(-) group. Our findings provide further evidence that a comprehensive impairment of cognitive functioning, especially a severe reduction in mental speed, remains after recovery from depression in patients with major depression and SCI.
Subject(s)
Cerebral Infarction/psychology , Cognition Disorders/etiology , Depressive Disorder/psychology , Aged , Brain/pathology , Cerebral Infarction/complications , Cognition Disorders/psychology , Cross-Sectional Studies , Depressive Disorder/complications , Depressive Disorder/drug therapy , Female , Humans , Intelligence , Magnetic Resonance Imaging , Male , Middle Aged , Psychiatric Status Rating Scales , Reaction Time , Remission Induction , Wechsler ScalesABSTRACT
Previously, we reported a relationship between silent cerebral infarction (SCI), as detected by magnetic resonance imaging (MRI), and late onset major depression. In the present study, we clarify the clinical features of the depressive phase of patients with major depression and SCI, and their response to antidepressant pharmacotherapy. Using clinical charts, we retrospectively examined patients with depression, who were first admitted for antidepressant pharmacotherapy. All patients were classified according to the MRI findings and the age on admission (older or younger than 50 years) into either the young SCI(-) group (n = 23), the elderly SCI(-) group (n = 27) or the elderly SCI(+) group (n = 20).The characteristics of the clinical features were evaluated at the time of admission, after 2 weeks of treatment and at the time of discharge using the Hamilton rating scale for depression (HAMD). These data were compared between each patient group. No differences in the clinical features, as evaluated by HAMD, were observed between the three groups at the time of admission. However, the mean length of treatment was significantly longer and the treatment response, as evaluated by the total HAMD score, was significantly worse in the elderly SCI(+) group than in the other two groups, when examined after 2 weeks of treatment and at the time of discharge. The elderly SCI(+) group demonstrated higher scores in feelings of guilt, suicide, retardation and hypochondriasis than the young SCI(-) group and the elderly SCI(-) group after two weeks of treatment, and higher scores in early insomnia, late insomnia, somatic anxiety and hypochondriasis at the time of discharge. Our findings suggest that while the presence of SCI does not affect the clinical features observed at the time of admission, it does affect the treatment response to antidepressant pharmacotherapy.
Subject(s)
Antidepressive Agents/therapeutic use , Cerebral Infarction/drug therapy , Depressive Disorder, Major/drug therapy , Adult , Age Factors , Aged , Antidepressive Agents/adverse effects , Cerebral Infarction/diagnosis , Cerebral Infarction/psychology , Cross-Sectional Studies , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/psychology , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Length of Stay , Magnetic Resonance Imaging , Male , Middle Aged , Personality Inventory , Retrospective Studies , Treatment OutcomeABSTRACT
Modulation of neurotrophic factors to protect neurons from damage is proposed as a novel mechanism for the action of antidepressants. However, the effect of antidepressants on modulation of glial cell line-derived neurotrophic factor (GDNF), which has potent and widespread effects, remains unknown. Here, we demonstrated that long-term use of antidepressant treatment significantly increased GDNF mRNA expression and GDNF release in time- and concentration-dependent manners in rat C6 glioblastoma cells. Amitriptyline treatment also increased GDNF mRNA expression in rat astrocytes. GDNF release continued for 24 h following withdrawal of amitriptyline. Furthermore, following treatment with antidepressants belonging to several different classes (amitriptyline, clomipramine, mianserin, fluoxetine and paroxetine) significantly increased GDNF release, but which did not occur after treatment with non-antidepressant psychotropic drugs (haloperidol, diazepam and diphenhydramine). Amitriptyline-induced GDNF release was inhibited by U0126 (10 microM), a mitogen-activated protein kinase (MAPK)-extracellular signal-related kinase (ERK) kinase (MEK) inhibitor, but was not inhibited by H-89 (1 microM), a protein kinase A inhibitor, calphostin C (100 nM), a protein kinase C inhibitor and PD 169316 (10 microM), a p38 mitogen-activated protein kinase inhibitor. These results suggested that amitriptyline-induced GDNF synthesis and release occurred at the transcriptional level, and may be regulated by MEK/MAPK signalling. The enhanced and prolonged induction of GDNF by antidepressants could promote neuronal survival, and protect neurons from the damaging effects of stress. This may contribute to explain therapeutic action of antidepressants and suggest new strategies of pharmacological intervention.
Subject(s)
Antidepressive Agents/pharmacology , Glioblastoma/metabolism , Nerve Growth Factors , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/metabolism , Sulfonamides , Amitriptyline/administration & dosage , Amitriptyline/pharmacology , Animals , Astrocytes/drug effects , Astrocytes/metabolism , Butadienes/pharmacology , Cell Line , Cells, Cultured , Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Glial Cell Line-Derived Neurotrophic Factor , Imidazoles/pharmacology , Isoquinolines/pharmacology , Kinetics , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Naphthalenes/pharmacology , Nerve Tissue Proteins/genetics , Nitriles/pharmacology , Protein Kinase C/antagonists & inhibitors , Psychotropic Drugs/pharmacology , Rats , p38 Mitogen-Activated Protein KinasesABSTRACT
RATIONALE: Lithium is the most widely prescribed mood stabilizer, but the precise mechanism of lithium is unresolved. OBJECTIVE: We examine the effects of the administration of therapeutically relevant concentrations of lithium on the expression of brain-derived neurotrophic factor (BDNF) and its receptor, Trk B, as well as glia-derived neurotrophic factor (GDNF) and its receptors, RET and GDNFR-alpha, in the rat brain. In addition, we also examined the effect of another well-prescribed mood stabilizer, valproate, on the expression of BDNF and GDNF. METHODS: Rats were kept on a 0.2% lithium carbonate-containing diet for 1, 7, 14, or 28 days or treated with valproate (400 mg/kg per day i.p.) for 1 or 14 days. After the brains were rapidly removed, the levels of BDNF, GDNF, and their receptors were measured by ELISA or western blot analysis. RESULTS: Chronic lithium treatment for 14 and 28 days significantly increased the expression of BDNF in the hippocampus and temporal cortex. In addition, chronic lithium treatment for 14 days significantly increased the expression of BDNF in the frontal cortex. In contrast, acute or chronic dietary lithium treatment did not alter GDNF expression in these brain regions. In addition, acute or chronic lithium treatments did not change the levels of Trk B, RET, or GDNFR-alpha immunoreactivity. As well as lithium, repeated administration of valproate also increased the expression of BDNF in the frontal cortex and hippocampus. CONCLUSIONS: Our results suggest that the chronic administration of mood stabilizers may produce a neurotrophic effect mediated by the upregulation of BDNF in the rat brain.