173 results
Search Results
102. Depression, Selective Serotonin Reuptake Inhibitors, and Osteoporosis.
- Author
-
Bab, Itai and Yirmiya, Raz
- Abstract
n increasing number of studies suggest an association between depression and osteoporosis. In a mouse model, depression induces bone loss, mediated by brain-to-bone sympathetic signaling. Depression and bone antianabolic sympathetic tone are alleviated by increasing central serotonin (5-hydroxytryptamine, 5-HT) levels. However, selective serotonin reuptake inhibitors (SSRIs), the first-line antidepressants, increase extracellular 5-HT levels but have deleterious skeletal effects. The skeletal serotonergic system consists of 5-HT receptors and the 5-HT transporter (5-HTT) in osteoblasts and osteocytes. 5-HTT is a transmembrane protein targeted by SSRIs. 5-HT restrains osteoblastic activity, thus leading to bone loss. Apparently, the negative skeletal effects of the peripheral SSRI-induced increase in 5-HT outweighs the skeletal benefits resulting from the enhanced central 5-HT antidepressant and antisympathetic activity. Overall, major depression appears as an important risk factor for osteoporosis. However, antidepressants, mainly SSRIs, should be evaluated in view of the causal relationship between depression and bone loss, and vis-à-vis their skeletal adverse effects. Patients with depressive disorders should undergo a routine skeletal evaluation and receive timely antiosteoporotic therapy, especially when SSRI treatment is prescribed. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
103. Switching to Hypomania and Mania: Differential Neurochemical, Neuropsychological, and Pharmacologic Triggers and Their Mechanisms.
- Author
-
Chen, Jun, Fang, Yiru, Kemp, David, Calabrese, Joseph, and Gao, Keming
- Abstract
Current data suggest that monoamines, acetylcholine, amino acids, cortisol, thyroid hormones, and melatonin may be involved in the pathophysiology of bipolar disorder (BPD). Any neuropsychological or pharmacologic factor causing a disturbance in these neurochemicals may trigger manic/hypomanic switching. Antidepressants, stimulants, anticholinergics, steroids, and thyroid hormone have been reported to cause treatment-emergent mania (TEM) in BPD, but only recently have the traditional antidepressants been systematically studied. Paroxetine, 20 mg/d, monotherapy in treatment of acute, relatively 'pure' bipolar I and II depression, and fluoxetine monotherapy in bipolar II depression conferred a similar risk as placebo for TEM. Paroxetine or bupropion adjunctive therapy to mood stabilizer(s) had a similar risk as placebo for treatment of TEM in real world patients with bipolar depression during continuation treatment. Venlafaxine was shown to have an increased risk of TEM compared with bupropion and sertraline. The evolving literature continues to support the role of mood stabilizers in preventing future mood episodes of BPD. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
104. Scopolamine Produces Larger Antidepressant and Antianxiety Effects in Women Than in Men.
- Author
-
Furey, Maura L., Khanna, Ashish, Hoffman, Elana M., and Drevets, Wayne C.
- Subjects
SCOPOLAMINE ,ANTIDEPRESSANTS ,TRANQUILIZING drugs ,MUSCARINIC agonists ,DEPRESSED persons ,PEOPLE with bipolar disorder ,PLACEBOS ,CLINICAL trials ,PSYCHOLOGY ,MEDICAL care - Abstract
Some antidepressant agents generate differential benefit based on gender. Blocking cholinergic muscarinic receptors using scopolamine produces robust and rapid antidepressant effects in males and females combined. This study evaluated if males and females differ in the antidepressant response magnitude following scopolamine administration. A total of 52 male and female outpatients meeting criteria for recurrent major depressive or bipolar disorder participated in a double-blind, randomized, placebo-controlled, crossover clinical trial involving seven i.v. infusions of placebo or scopolamine (4 μg/kg). Following a single-blind placebo lead-in, participants entered either a placebo-block/scopolamine-block or a scopolamine-block/placebo-block sequence. Each block included three sessions. Clinical ratings were acquired before each infusion and included the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Rating Scale (HAM-A). A treatment group × block interaction (F=21.0, p<0.001) was observed in MADRS scores across gender, and the reduction was significant by the evaluation following the first scopolamine administration (F=8.4, p=0.006). The treatment group × block interaction was also significant in males (F=3.8, p=0.043) and females (F=35.6, p<0.001) separately. A block × gender interaction (F=7.4, p=0.009) indicated that the response magnitude was larger in women. The treatment × block interaction was significant for the HAM-A across gender (F=12.0, p<0.001), and was significant for females (F=24.9, p<0.001) but not for males (F=1.3, p=0.30). When comparing the baseline block to study end, the block × gender interaction (F=12.6, p=0.001) showed that the antianxiety response was greater in women. Men and women show a rapid antidepressant response following scopolamine, but the magnitude of response is larger in women than in men. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
105. Peripheral BDNF Produces Antidepressant-Like Effects in Cellular and Behavioral Models.
- Author
-
Schmidt, Heath D. and Duman, Ronald S.
- Subjects
MENTAL depression ,ANTIDEPRESSANTS ,SERUM ,ANHEDONIA ,DEVELOPMENTAL neurobiology ,HIPPOCAMPUS (Brain) - Abstract
Recent clinical studies demonstrate that serum levels of brain-derived neurotrophic factor (BDNF) are significantly decreased in patients with major depressive disorder (MDD) and that antidepressant treatments reverse this effect, indicating that serum BDNF is a biomarker of MDD. These findings raise the possibility that serum BDNF may also have effects on neuronal activity and behavior, but the functional significance of altered serum BDNF is unknown. To address this issue, we determined the influence of peripheral BDNF administration on depression- and anxiety-like behavior, including the forced swim test (FST), chronic unpredictable stress (CUS)/anhedonia, novelty-induced hypophagia (NIH) test, and elevated-plus maze (EPM). Furthermore, we examined adult hippocampal neurogenesis as well as hippocampal and striatal expression of BDNF, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), in order to determine whether peripherally administered BDNF produces antidepressant-like cellular responses in the brain. Peripheral BDNF administration increased mobility in the FST, attenuated the effects of CUS on sucrose consumption, decreased latency in the NIH test, and increased time spent in the open arms of an EPM. Moreover, adult hippocampal neurogenesis was increased after chronic, peripheral BDNF administration. We also found that BDNF levels as well as expression of pCREB and pERK were elevated in the hippocampus of adult mice receiving peripheral BDNF. Taken together, these results indicate that peripheral/serum BDNF may not only represent a biomarker of MDD, but also have functional consequences on molecular signaling substrates, neurogenesis, and behavior. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
106. Docosahexaenoic Acid Suppresses Neuroinflammatory Responses and Induces Heme Oxygenase-1 Expression in BV-2 Microglia: Implications of Antidepressant Effects for Omega-3 Fatty Acids.
- Author
-
Dah-Yuu Lu, Yin-Yin Tsao, Yuk-Man Leung, and Kuan-Pin Su
- Subjects
DEPRESSED persons ,PEOPLE with mental illness ,ANTIDEPRESSANTS ,INFLAMMATION ,PATHOLOGY - Abstract
Accumulating evidence suggests that the pathophysiology of depression might be associated with neuroinflammation, which could be attenuated by pharmacological treatment for depression. Omega-3 polyunsaturated fatty acids (PUFAs) are anti-inflammatory and exert antidepressant effects. The aim of this study was to identify the molecular mechanisms through which docosahexaenoic acid (DHA), the main omega-3 PUFA in the brain, modulates oxidative reactions and inflammatory cytokine production in microglial and neuronal cells. The results of this study showed that DHA reduced expressions of tumor necrosis factor-α, interleukin-6, nitric oxide synthase, and cyclo-oxygenase-2, induced by interferon-γ, and induced upregulation of heme oxygenase-1 (HO-1) in BV-2 microglia. The inhibitory effect of DHA on nitric oxide production was abolished by HO-1 inhibitor zinc protoporphyrin IX. In addition, DHA caused AKT and ERK activation in a time-dependent manner, and the DHA-induced HO-1 upregulation could be attenuated by PI-3 kinase/AKT and MEK/ERK inhibitors. DHA also increased IKKα/β phosphorylation, IκBα phosphorylation, and IκBα degradation, whereas both nuclear factor-κB and IκB protease inhibitors could inhibit DHA-induced HO-1 expressions. The other major n-3 PUFA, eicosapentaenoic acid, showed similar effects of DHA on inflammation and HO-1 in repeated key experiments. In connecting with inflammation hypothesis of depression and clinical studies supporting the antidepressant effects of omega-3 PUFAs, this study provides a novel implication of the antidepressant mechanisms of DHA. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
107. Cabergoline, a dopamine receptor agonist, has an antidepressant-like property and enhances brain-derived neurotrophic factor signaling.
- Author
-
Chiba, Shuichi, Numakawa, Tadahiro, Ninomiya, Midori, Yoon, Hyung, and Kunugi, Hiroshi
- Subjects
DOPAMINE agonists ,ANTIDEPRESSANTS ,NEUROTROPHINS ,LOCOMOTION ,THERAPEUTICS ,MENTAL depression ,LABORATORY rats - Abstract
Dopamine agonists have been implicated in the treatment of depression. Cabergoline is an ergot derivative with a high affinity to dopamine D
2 -like receptors; however, there have been few preclinical studies on its antidepressant-like effects. Behavioral effects of cabergoline were examined in rats using forced swimming (FST), novelty-suppressed feeding (NST), open field (OFT), and elevated-plus maze (EPT) tests. In a single treatment paradigm, behaviors of rats were analyzed 4 h after single injection of cabergoline (s.c., 0–4 µmol/kg). In a repeated-treatment paradigm, OFT, EPT, and FST were conducted on days 11, 12, and13–14, respectively, during daily cabergoline injections (s.c., 0.5 µmol/kg), and then hippocampus was removed 24 h after the last injection. NST was conducted in a separate experiment at day 14. Western blotting was used for the analysis of the protein levels of brain-derived neurotrophic factor (BDNF) and the activation of intracellular signaling molecules. Single injection of cabergoline demonstrated decreased immobility in FST and distance traveled during 0–10 min in OFT, while time spent and entry into open arms were increased at 4 µmol/kg. When cabergoline was repeatedly administered, immobility in FST and the latency of feeding in NSF were significantly reduced, while vertical movement was increased in OFT. The time in closed arms was tended to be decreased in EPT. Expression of BDNF and activation of extracellular signal-regulated kinase 1 were up-regulated after the chronic administration of cabergoline. Cabergoline exerts antidepressant- and anxiolytic-like effects, which may be mediated by potentiation of intracellular signaling of BDNF. [ABSTRACT FROM AUTHOR]- Published
- 2010
- Full Text
- View/download PDF
108. Effects of baclofen and mirtazapine on a laboratory model of marijuana withdrawal and relapse.
- Author
-
Haney, Margaret, Hart, Carl, Vosburg, Suzanne, Comer, Sandra, Reed, Stephanie, Cooper, Ziva, and Foltin, Richard
- Subjects
WITHDRAWAL (Psychology) ,MARIJUANA abuse ,DISEASE relapse ,TEMPERANCE ,MEDICATION therapy management ,MOOD (Psychology) - Abstract
Only a small percentage of individuals seeking treatment for their marijuana use achieves sustained abstinence, suggesting more treatment options are needed. We investigated the effects of baclofen (study 1) and mirtazapine (study 2) in a human laboratory model of marijuana intoxication, withdrawal, and relapse. In study 1, daily marijuana smokers ( n = 10), averaging 9.4 (±3.9) marijuana cigarettes/day, were maintained on placebo and each baclofen dose (60, 90 mg/day) for 16 days. In study 2, daily marijuana smokers ( n = 11), averaging 11.9 (±5.3) marijuana cigarettes/day, were maintained on placebo and mirtazapine (30 mg/day) for 14 days each. Medication administration began outpatient prior to each 8-day inpatient phase. On the first inpatient day of each medication condition, participants smoked active marijuana (study 1: 3.3% THC; study 2: 6.2% THC). For the next 3 days, they could self-administer placebo marijuana (abstinence phase), followed by 4 days in which they could self-administer active marijuana (relapse phase); participants paid for self-administered marijuana using study earnings. In study 1, during active marijuana smoking, baclofen dose-dependently decreased craving for tobacco and marijuana, but had little effect on mood during abstinence and did not decrease relapse. Baclofen also worsened cognitive performance regardless of marijuana condition. In study 2, mirtazapine improved sleep during abstinence, and robustly increased food intake, but had no effect on withdrawal symptoms and did not decrease marijuana relapse. Overall, this human laboratory study did not find evidence to suggest that either baclofen or mirtazapine showed promise for the potential treatment of marijuana dependence. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
109. Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients.
- Author
-
Miskowiak, Kamilla W., Favaron, Elisa, Hafizi, Sepehr, Inkster, Becky, Goodwin, Guy M., Cowen, Philip J., and Harmer, Catherine J.
- Subjects
ERYTHROPOIETIN ,NEUROPROTECTIVE agents ,NEUROTROPHIC functions ,PERINATAL mood & anxiety disorders ,ANTIDEPRESSANTS ,HIPPOCAMPUS diseases ,THERAPEUTICS - Abstract
Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers. The current study investigates the effects of Epo on the neural and cognitive response to emotional facial expressions in depressed patients. Nineteen acutely depressed patients were randomized to receive Epo (40,000 IU) or saline intravenously in a double-blind, parallel-group design. On day 3, we assessed neuronal responses to fearful and happy faces using functional magnetic resonance imaging and measured facial expression recognition after the scan. Epo reduced neural response to fearful vs. happy faces in the amygdala and hippocampus, and to fearful faces vs. baseline in superior temporal and occipitoparietal regions 3 days after administration in acutely depressed patients. This was accompanied by a specific reduction in the recognition of fear in Epo-treated patients after the scan similar to the effects on face recognition seen with antidepressant drug treatment. The present findings are similar to the effects of conventional antidepressants in acutely depressed patients and opposite to hypervigilance to negative facial expressions in depression. This highlights a potential antidepressant mechanism and warrants further investigation of Epo as a new candidate compound for treatment of depression. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
110. Antidepressant- and anxiolytic effects of the novel melatonin agonist Neu-P11 in rodent models.
- Author
-
Shao-wen TIAN, Moshe LAUDON, Li HAN, Jun GAO, Fu-lian HUANG, Yu-feng YANG, and Hai-feng DENG
- Subjects
ANTIDEPRESSANTS ,MELATONIN ,ANXIETY ,TRANQUILIZING drugs ,MAZE tests ,MENTAL depression - Abstract
AbstractAim:To investigate the potential antidepressant and anxiolytic effects of Neu-P11, a novel melatonin agonist, in two models of depression in rats and a model of anxiety in mice.Methods:In the learned helplessness test (LH), Neu-P11 or melatonin (25–100 mg/kg, ip) was administered to rats 2 h before the beginning of the dark phase once a day for 5 days and the number of escape failures and intertrial crossings during the test phase were recorded. In the forced swimming test (FST), rats received a single or repeated administration of Neu-P11 (25–100 mg/kg, ip). The total period of immobility during the test phase was assessed. In the elevated plus-maze test (EPM), mice were treated with Neu-P11 (25–100 mg/kg, ip) or melatonin in the morning or in the evening and tested 2 h later. The percentage of time spent in the open arms and the open arms entries were assessed.Results:In the LH test, Neu-P11 but not melatonin significantly decreased the escape deficit and had no effect on the intertrial crossings. In the FST, a single or repeated administration of Neu-P11, either in the morning or in the evening, significantly decreased the duration of immobility. In the EPM test, Neu-P11 significantly increased the percentage of time spent in the open arms and the open arms entries irrespective to the time of administration. Melatonin was effective only when administered in the afternoon.Conclusion:The results demonstrate that Neu-P11 exerts antidepressant and anxiolytic activities in rodent models. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
111. Assessing the antidepressant-like effects of carbetocin, an oxytocin agonist, using a modification of the forced swimming test.
- Author
-
Chaviaras, Stella, Mak, Plato, Ralph, David, Krishnan, Lalitha, and Broadbear, Jillian
- Subjects
OXYTOCIN & psychology ,NEUROPEPTIDES ,CEREBRAL cortex ,INTRAPERITONEAL injections ,ANTIDEPRESSANTS ,CENTRAL nervous system ,PSYCHOPHARMACOLOGY ,PSYCHOLOGY - Abstract
The distribution of oxytocin receptors in limbic regions, as well as evidence that exogenous oxytocin modulates affect and fear processing, suggests that this neuropeptide may have a role to play in the treatment of mood disorders. This study compared the effects of acute treatment with the oxytocin receptor agonist, carbetocin with the tricyclic antidepressant, imipramine, using male Sprague–Dawley rats. Intracerebroventricular (i.c.v.; 1, 10, 100 μg/rat), intravenous (i.v.; 2.5, 5 mg/kg), and intraperitoneal (i.p.; 2, 6.4, 20 mg/kg) carbetocin and imipramine (1.8, 5.6, 10 mg/kg, i.p.) were examined in the modified forced swim and open field tests. The mechanism of action of carbetocin was investigated by co-administering it with the oxytocin antagonist, atosiban, either centrally (5 μg/rat, i.c.v.) or systemically (1 mg/kg, i.v.). Imipramine and carbetocin (all three routes of administration) both significantly reduced immobility and increased swimming and/or climbing behavior in the forced swim test. The systemic effects of carbetocin were blocked by central and systemic atosiban co-administration. Only amphetamine (2 mg/kg, i.p.), included as a false positive in order to distinguish whether antidepressant-like effects were due to psychomotor stimulation, increased locomotor activity in the open field test. Carbetocin produced antidepressant-like changes in behavior via activation of oxytocin receptors in the CNS. The similarities between imipramine and carbetocin in the forced swim test suggest that drugs which target the oxytocinergic system may aid both the understanding and pharmacological treatment of depressive illness. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
112. The involvement of NMDA and AMPA receptors in the mechanism of antidepressant-like action of zinc in the forced swim test.
- Author
-
Szewczyk, B., Poleszak, E., Sowa-Kućma, M., Wróbel, A., Slotwiński, S., Listos, J., Wlaź, P., Cichy, A., Siwek, A., Dybala, M., Gołembiowska, K., Pilc, A., and Nowak, Gabriel
- Subjects
METHYL aspartate ,ANTIDEPRESSANTS ,ZINC ,MICE ,RATS - Abstract
Antidepressant-like activity of zinc in the forced swim test (FST) was demonstrated previously. Enhancement of such activity by joint administration of zinc and antidepressants was also shown. However, mechanisms involved in this activity have not yet been established. The present study examined the involvement of the NMDA and AMPA receptors in zinc activity in the FST in mice and rats. Additionally, the influence of zinc on both glutamate and aspartate release in the rat brain was also determined. Zinc-induced antidepressant-like activity in the FST in both mice and rats was antagonized by N-methyl- d-aspartic acid (NMDA, 75 mg/kg, i.p.) administration. Moreover, low and ineffective doses of NMDA antagonists (CGP 37849, L-701,324, d-cycloserine, and MK-801) administered together with ineffective doses of zinc exhibit a significant reduction of immobility time in the FST. Additionally, we have demonstrated the reduction of immobility time by AMPA receptor potentiator, CX 614. The antidepressant-like activity of both CX 614 and zinc in the FST was abolished by NBQX (an antagonist of AMPA receptor, 10 mg/kg, i.p.), while the combined treatment of sub-effective doses of zinc and CX 614 significantly reduces the immobility time in the FST. The present study also demonstrated that zinc administration potentiated a veratridine-evoked glutamate and aspartate release in the rat’s prefrontal cortex and hippocampus. The present study further suggests the antidepressant properties of zinc and indicates the involvement of the NMDA and AMPA glutamatergic receptors in this activity. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
113. Ozone modulates the effects of imipramine on immobility in the forced swim test, and nonspecific parameters of hippocampal oxidative stress in the rat.
- Author
-
Mokoena, Mmalebuso L., Harvey, Brian H., Oliver, Douglas W., and Brink, Christiaan B.
- Subjects
OZONE ,IMIPRAMINE ,HIPPOCAMPUS (Brain) ,OXIDATIVE stress ,ANTIDEPRESSANTS - Abstract
Depression has been associated with oxidative stress. There is increased awareness of the role of environmental toxins in the development of mood disorders. Ozone, a pro-oxidant and environmental pollutant, has been noted to have central nervous system effects. We investigated the effects of acute and chronic ozone inhalation on the response of imipramine in the forced-swim test (FST) and on biomarkers of oxidative stress in rat hippocampus. Sprague Dawley rats were exposed to 0, 0.25 or 0.7 ppm ozone per inhalation 4 h daily for either 30 days (chronic) or once (acute). Animals were then injected intraperitoneally with imipramine (10 mg/kg) or saline 24, 5 and 1 h before the forced-swim test. Hippocampal superoxide accumulation and lipid peroxidation were measured. Imipramine evoked an antidepressant-like effect independent of acute or chronic ozone exposure. However, 0.7 ppm acute ozone and 0.25 ppm chronic ozone attenuated the antidepressant-like effects of imipramine. The ozone exposures also elevated hippocampal superoxide accumulation and lipid peroxidation. Importantly, imipramine reversed the lipid peroxidation induced by chronic ozone, thereby preventing cellular damage induced by oxidative stress. Ozone exposure presents a feasible model with etiological validity to investigate oxidative stress in depression and antidepressant action. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
114. Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole.
- Author
-
Banasr, M., Chowdhury, G. M. I., Terwilliger, R., Newton, S. S., Duman, R. S., Behar, K. L., and Sanacora, G.
- Subjects
NEUROGLIA ,NEUROTRANSMITTERS ,MENTAL depression ,GLUTAMIC acid ,PREFRONTAL cortex - Abstract
Growing evidence indicates that glia pathology and amino-acid neurotransmitter system abnormalities contribute to the pathophysiology and possibly the pathogenesis of major depressive disorder. This study investigates changes in glial function occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Furthermore, we analyzed the effects of riluzole, a Food and Drug Administration-approved drug for the treatment of amyotrophic laterosclerosis, known to modulate glutamate release and facilate glutamate uptake, on CUS-induced glial dysfunction and depressive-like behaviors. We provide the first experimental evidence that chronic stress impairs cortical glial function. Animals exposed to CUS and showing behavioral deficits in sucrose preference and active avoidance exhibited significant decreases in
13 C-acetate metabolism reflecting glial cell metabolism, and glial fibrillary associated protein (GFAP) mRNA expression in the PFC. The cellular, metabolic and behavioral alterations induced by CUS were reversed and/or blocked by chronic treatment with the glutamate-modulating drug riluzole. The beneficial effects of riluzole on CUS-induced anhedonia and helplessness demonstrate the antidepressant action of riluzole in rodents. Riluzole treatment also reversed CUS-induced reductions in glial metabolism and GFAP mRNA expression. Our results are consistent with recent open-label clinical trials showing the drug's effect in mood and anxiety disorders. This study provides further validation of hypothesis that glial dysfunction and disrupted amino-acid neurotransmission contribute to the pathophysiology of depression and that modulation of glutamate metabolism, uptake and/or release represent viable targets for antidepressant drug development. [ABSTRACT FROM AUTHOR]- Published
- 2010
- Full Text
- View/download PDF
115. The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation.
- Author
-
McEwen, B. S., Chattarji, S., Diamond, D. M., Jay, T. M., Reagan, L. P., Svenningsson, P., and Fuchs, E.
- Subjects
ANTIDEPRESSANTS ,MENTAL depression ,GLUTAMIC acid ,NEUROPLASTICITY ,MENTAL illness - Abstract
Tianeptine is a clinically used antidepressant that has drawn much attention, because this compound challenges traditional monoaminergic hypotheses of depression. It is now acknowledged that the antidepressant actions of tianeptine, together with its remarkable clinical tolerance, can be attributed to its particular neurobiological properties. The involvement of glutamate in the mechanism of action of the antidepressant tianeptine is consistent with a well-developed preclinical literature demonstrating the key function of glutamate in the mechanism of altered neuroplasticity that underlies the symptoms of depression. This article reviews the latest evidence on tianeptine's mechanism of action with a focus on the glutamatergic system, which could provide a key pathway for its antidepressant action. Converging lines of evidences demonstrate actions of tianeptine on the glutamatergic system, and therefore offer new insights into how tianeptine may be useful in the treatment of depressive disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
116. Valproate and Amitriptyline Exert Common and Divergent Influences on Global and Gene Promoter-Specific Chromatin Modifications in Rat Primary Astrocytes.
- Author
-
Perisic, Tatjana, Zimmermann, Nicole, Kirmeier, Thomas, Asmus, Maria, Tuorto, Francesca, Uhr, Manfred, Holsboer, Florian, Rein, Theo, and Zschocke, Jürgen
- Subjects
VALPROIC acid ,AMITRIPTYLINE ,ADRENERGIC uptake inhibitors ,ANTIDEPRESSANTS ,PSYCHIATRIC drugs ,VENLAFAXINE - Abstract
Aberrant biochemical processes in the brain frequently go along with subtle shifts of the cellular epigenetic profile that might support the pathogenic progression of psychiatric disorders. Although recent reports have implied the ability of certain antidepressants and mood stabilizers to modulate epigenetic parameters, studies comparing the actions of these compounds under the same conditions are lacking. In this study, we screened amitriptyline (AMI), venlafaxine, citalopram, as well as valproic acid (VPA), carbamazepine, and lamotrigine for their potential actions on global and local epigenetic modifications in rat primary astrocytes. Among all drugs, VPA exposure evoked the strongest global chromatin modifications, including histone H3/H4 hyperacetylation, 2MeH3K9 hypomethylation, and DNA demethylation, as determined by western blot and luminometric methylation analysis, respectively. CpG demethylation occurred independently of DNA methyltransferase (DNMT) suppression. Strikingly, AMI also induced slight cytosine demethylation, paralleled by the reduction in DNMT enzymatic activity, without affecting the global histone acetylation status. Locally, VPA-induced chromatin modifications were reflected at the glutamate transporter (GLT-1) promoter as shown by bisulfite sequencing and acetylated histone H4 chromatin immunoprecipitation analysis. Distinct CpG sites in the distal part of the GLT-1 promoter were demethylated and enriched in acetylated histone H4 in response to VPA. For the first time, we could show that these changes were associated with an enhanced transcription of this astrocyte-specific gene. In contrast, AMI failed to stimulate GLT-1 transcription and to alter promoter methylation levels. In conclusion, VPA and AMI globally exerted chromatin-modulating activities using different mechanisms that divergently precipitated at an astroglial gene locus. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
117. GABA transporter lysine 448: a key residue for tricyclic antidepressants interaction.
- Author
-
Cherubino, Francesca, Miszner, Andreea, Renna, Maria Daniela, Sangaletti, Rachele, Giovannardi, Stefano, and Bossi, Elena
- Subjects
ANTIDEPRESSANTS ,SEROTONIN uptake inhibitors ,ELECTROPHYSIOLOGY ,XENOPUS laevis ,GLUTAMIC acid - Abstract
The effects of three tricyclic antidepressants (TCAs) and two serotonin selective reuptake inhibitors (SSRIs) have been studied with an electrophysiological approach on Xenopus laevis oocytes expressing the rat GABA (γ-Aminobutyric-acid) transporter rGAT1. All tested TCAs and SSRIs inhibit the GABA-associated current in a dose-dependent way with low but comparable efficacy. The pre-steady-state and uncoupled currents appear substantially unaffected. The efficacy of desipramine, but not of the other drugs, is strongly increased in the lysine-glutamate or -aspartate mutants K448E and K448D. Comparison of I
max and K0.5GABA in the absence and presence of desipramine showed that both parameters are reduced by the drug in the wild-type and in the K448E mutant. This suggests an uncompetitive inhibition, in which the drug can bind only after the substrate, an explanation in agreement with the lack of effects on the pre-steady-state and leak currents, and with the known structural data. [ABSTRACT FROM AUTHOR]- Published
- 2009
- Full Text
- View/download PDF
118. Do stressful life events predict medical treatment outcome in first episode of depression?
- Author
-
Bock, Camilla, Bukh, Jens D., Vinberg, Maj, Gether, Ulrik, and Kessing, Lars V.
- Subjects
DEPRESSED persons ,MEDICAL care ,PSYCHIATRIC hospitals ,ANTIDEPRESSANTS ,PERSONALITY disorders - Abstract
It is unclear whether medical treatment outcome in first episode depression differ for patients with and without stressful life events prior to onset of depression. Patients discharged with a diagnosis of a single depressive episode from a psychiatric in- or outpatient hospital setting were consecutively sampled from the Danish Psychiatric Central Research Register. Patients participated in an extensive interview including the schedules for clinical assessment in neuropsychiatry (SCAN), the Structured Clinical Interview for DSM-IV axis II personality disorders (SCID-II) and the interview of recent life events (IRLE). Medical treatment history was assessed in detail using standardised procedures (TRAQ). Remission was defined as a score ≤ 7 on the Hamilton Depression Rating Scale, 17 items and a score ≥ 4 on TRAQ following (1) first trial of antidepressant treatment (2) two adequate trials of antidepressant treatment. A total of 399 patients participated in the interview and among these 301 patients obtained a SCAN diagnosis of a single depressive episode. A total of 62.8% of the 301 patients experienced at least one moderate to severe stressful life event in a 6 months period prior to symptom onset. The presence of a stressful life event or the number of stressful life events did not predict remission from first or second antidepressant drug trial—nor when adjusted for differences in age, gender or prevalence of co-morbid personality disorders. Medical treatment outcome in first episode depression does not depend on the prevalence of moderate to severe stressful life events prior to symptom onset. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
119. DFT and electrochemical studies on nortriptyline oxidation sites.
- Author
-
de Toledo, Renata A., Santos, Mauro C., Suffredini, Hugo B., Homem-de-Mello, Paula, Honorio, Kathia M., and Mazo, Luiz H.
- Published
- 2009
- Full Text
- View/download PDF
120. Genetic and Clinical Predictors of Sexual Dysfunction in Citalopram-Treated Depressed Patients.
- Author
-
Perlis, Roy H., Laje, Gonzalo, Smoller, Jordan W., Fava, Maurizio, Rush, A. John, and McMahon, Francis J.
- Subjects
SEXUAL dysfunction ,SEROTONIN uptake inhibitors ,ORGASMIC dysfunction ,SEROTONIN ,IMPOTENCE - Abstract
Sexual dysfunction is a major contributor to treatment discontinuation and nonadherence among patients treated with selective serotonin reuptake inhibitors (SSRIs). The mechanisms by which depressive symptoms in general, as well as SSRI exposure in particular, may worsen sexual function are not known. We examined genetic polymorphisms, including those of the serotonin and glutamate systems, for association with erectile dysfunction, anorgasmia, and decreased libido during citalopram treatment. Clinical data were drawn from a nested case–control cohort derived from the STAR
* D study, a multicenter, prospective, effectiveness trial in outpatients with nonpsychotic major depressive disorder (MDD). Self-reports of erectile dysfunction, decreased libido, or difficulty achieving orgasm based on the Patient-Rated Inventory of Side Effects were examined among Caucasian subjects (n=1473) for whom DNA and adverse effect measures were available, and who were treated openly with citalopram for up to 14 weeks. Of 1473 participants, 799 (54%) reported decreased libido; 525 (36%) reported difficulty achieving orgasm. Of 574 men, 211 (37%) reported erectile dysfunction. Using a set-based test for association, single nucleotide polymorphisms in glutamatergic genes were associated with decreased libido (GRIA3; GRIK2), difficulty achieving orgasm (GRIA1), and difficulty achieving erection (GRIN3A) (experiment-wide permuted p<0.05 for each). Evidence of association persisted after adjustment for baseline clinical and sociodemographic differences. Likewise, evidence of association was similar when the cohort was limited to those who did not report a given adverse event at the first post-baseline visit (ie, those whose adverse events were known to be treatment emergent). These hypothesis-generating analyses suggest the potential for glutamatergic treatment targets for sexual dysfunction during major depressive episodes.Neuropsychopharmacology (2009) 34, 1819–1828; doi:10.1038/npp.2009.4; published online 18 March 2009 [ABSTRACT FROM AUTHOR]- Published
- 2009
- Full Text
- View/download PDF
121. Acute Stress Responsiveness of the Neurotrophin BDNF in the Rat Hippocampus is Modulated by Chronic Treatment with the Antidepressant Duloxetine.
- Author
-
Molteni, Raffaella, Calabrese, Francesca, Cattaneo, Annamaria, Mancini, Michele, Gennarelli, Massimo, Racagni, Giorgio, and Riva, Marco A.
- Subjects
NEUROPLASTICITY ,ANTIDEPRESSANTS ,PSYCHOLOGICAL stress ,HIPPOCAMPUS (Brain) ,NEUROPSYCHOPHARMACOLOGY - Abstract
Compelling evidence suggests that mood disorders are characterized by reduced neuronal plasticity that might be normalized by pharmacological intervention. Our study aimed to establish whether chronic antidepressant treatment could alter the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) under a stressful condition. Therefore, adult male Sprague–Dawley rats were treated for 21 days with vehicle or with the SNRI duloxetine and, 24 h after the last injection, exposed to an acute swim stress (5 min) before being killed 15 min later. We found that chronic duloxetine treatment was able to modulate the rapid transcriptional changes of BDNF isoforms produced by an acute swim stress. Indeed whereas the mRNA levels of BDNF exon IV were upregulated by stress in vehicle as well as in duloxetine-treated rats, a significant increase of exon VI and exon IX was only found in rats that were pretreated with the antidepressant. These differential effects are in part because of selective changes in signaling pathways involved in the control of BDNF transcription. Moreover, the acute stressful episode significantly increased the levels of mature BDNF protein in the synaptosomal compartment in rats that were pretreated with the antidepressant, but not in control animals. Our results suggest that chronic antidepressant treatment might affect the responsiveness of BDNF under stressful conditions, suggesting that pharmacological intervention could ‘prime’ neuroprotective pathways and render them more responsive to preserve cell function and viability.Neuropsychopharmacology (2009) 34, 1523–1532; doi:10.1038/npp.2008.208; published online 19 November 2008 [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
122. Cost-effectiveness of transcranial magnetic stimulation in the treatment of major depression: a health economics analysis.
- Author
-
Simpson, Kit, Welch, Mary, Kozel, F., Demitrack, Mark, and Nahas, Ziad
- Abstract
Transcranial magnetic stimulation (TMS) is a novel antidepressant therapy shown to be effective and safe in pharmacotherapy-resistant major depression. The incremental cost-effectiveness and the direct cost burden compared with sham treatment were estimated, and compared with the current standard of care. Healthcare resource utilization data were collected during a multicenter study ( n=301) and a decision analysis was used to stratify the 9-week treatment outcomes. A Markov model with an acute-outcome severity-based risk of relapse was used to estimate the illness course over a full year of treatment follow-up. These model estimates were also compared to best estimates of outcomes and costs of pharmacotherapy treatment, using the published STAR
* D outcomes. The cost-effectiveness of TMS was described using an incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained and on a direct cost per patient basis across a varying range of assumptions. The model’s sensitivities to costs due to losses in work productivity and to caregiver time were also examined. Compared with sham treatment and at a cost of US$300 per treatment session, TMS provides an ICER of US$34,999 per QALY, which is less than the “willingness-to-pay’ standard of US$50,000 per QALY for a new treatment for major depression. When productivity gains due to clinical recovery were included, the ICER was reduced to US$6667 per QALY. In open-label conditions, TMS provided a net cost saving of US$1123 per QALY when compared with the current standard of care. In the openlabel condition, cost savings increased further when the costs for productivity losses were included in the model (net savings of US$7621). The overall cost benefits of treating MD using TMS were greater in those patients at the earliest levels of treatment resistance in the overall sample. TMS is a cost-effective treatment for patients who have failed to receive sufficient benefit from initial antidepressant pharmacotherapy. When used at earlier levels of treatment resistance, significant cost savings may be expected relative to the current standard of care. [ABSTRACT FROM AUTHOR]- Published
- 2009
- Full Text
- View/download PDF
123. Antidepressant effect of Melissa officinalis in the forced swimming test.
- Author
-
Emamghoreishi, M. and Talebianpour, M. S.
- Subjects
LEMON balm ,LAMIACEAE ,ANTIDEPRESSANTS ,PLANT extracts ,ESSENTIAL oils ,FLUOXETINE ,IMIPRAMINE - Abstract
Background: In Iranian and other traditional medicines, an antidepressant effect has been indicated for Melissa officinalis (Lamiaceae). However, studies showing its antidepressant effect is lacking. Therefore, the present study was undertaken to examine whether the aqueous extract and essential oil from leaves of Melissa officinalis have an antidepressant-like activity in mice. Materials and Methods: The effect of subchronic administration of different doses of the aqueous extract (25, 75, 150, 300 mg/kg or water; n=9-10) and the essential oil (10, 25, 75, 150, 300 mg/kg or almond oil; n=9-10) on immobility, climbing, and swimming behaviors were evaluated in the forced swimming test. Fluoxetine (20mg/kg) and imipramine (15 mg/kg) were used as reference drugs. Additionally, the effect of both plant preparations on spontaneous activity was examined. Results: All doses of the aqueous extract, used in this study, produced a significant reduction in immobility along with an increase in climbing behavior which is similar to those which have been observed with imipramine. Essential oil caused a dose-dependent reduction in immobility and an increase in climbing at all studied doses, compared to control group. Only the highest dose (300mg/kg) of essential oil showed a significant increase in swimming behavior. The aqueous extract, but not the essential oil, decreased spontaneous activity in a dose dependent manner. Conclusion: The results of this study suggests that the Melissa officinalis possess an antidepressant-like activity similar to imipramine which may have a potential clinical value for treatment of depression. [ABSTRACT FROM AUTHOR]
- Published
- 2009
124. Basal and stress-induced modulation of activity-regulated cytoskeletal associated protein (Arc) in the rat brain following duloxetine treatment.
- Author
-
Molteni, Raffaella, Calabrese, Francesca, Mancini, Michele, Racagni, Giorgio, and Riva, Marco
- Subjects
ANTIDEPRESSANTS ,BASAL metabolism ,CYTOSKELETAL proteins ,PREFRONTAL cortex - Abstract
Therapeutic efficacy of antidepressant drugs appears to be related to their ability in producing neuroadaptive changes that restore normal brain function. Activity-regulated cytoskeletal associated protein (Arc) is an effector immediate early gene that plays a fundamental role in activity-dependent neural plasticity in corticolimbic brain regions and has been implicated in the modulation of several functions known to be profoundly perturbed in depressive states. In the present study, we investigated transcriptional and translational changes of Arc in response to acute or chronic treatment with the novel antidepressant duloxetine. Although a limited increase of Arc messenger RNA (mRNA) levels was found in some structures after acute antidepressant administration, a marked up-regulation of its gene expression was found after chronic treatment, primarily at the level of frontal cortex. The changes observed after prolonged duloxetine administration strongly correlates with those previously reported on brain-derived neurotrophic factor mRNA levels Calabrese et al. (Neuropsychopharmacol 32:2351–2359, ). In addition, we found an anatomical-specific influence of chronic duloxetine on stress-dependent Arc modulation, which was limited to the frontal cortex. We suggest that these neuroadaptive changes, among others, might contribute to the normalization of neuroplastic defects associated with mood disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
125. Glycogen synthase kinase-3β gene is associated with antidepressant treatment response in Chinese major depressive disorder.
- Author
-
Tsai, S.-J., Liou, Y.-J., Hong, C.-J., Yu, Y.W.-Y., and Chen, T.-J.
- Subjects
GLYCOGEN ,PATIENTS ,FLUOXETINE ,GENES ,ANTIDEPRESSANTS - Abstract
Evidence suggests that glycogen synthase kinase-3β (GSK3B) activity is increased significantly in the brain of patients with major depressive disorders (MDD). Inhibition of GSK3B is thought to be a key feature in the therapeutic mechanism of antidepressants. To investigate whether common genetic variants in the GSK3B gene are associated with MDD and the therapeutic response to antidepressants, four polymorphisms (rs334558 (−50 T>C), rs13321783 (IVS7+9227 A>G), rs2319398 (IVS7+11660 G>T) and rs6808874 (IVS11+4251 T>A)) of the GSK3B gene were genotyped in 230 Chinese MDD patients and 415 controls. Among the MDD patients, 168 accepted selective serotonin reuptake inhibitor (SSRI) (fluoxetine or citalopram) antidepressant treatment and therapeutic evaluation for 4 weeks and 117 for 8 weeks. Significant association with MDD was not shown in the alleles and genotypes of single loci or four-locus haplotypes. However, three of the four polymorphisms investigated were significantly associated with 4-week antidepressant therapeutic effect (P=0.002–0.011). Of the four-locus haplotype analysis, the GSK3B TAGT carriers showed a poorer response to antidepressants in 4-week (P<0.0001) and 8-week (P=0.015) evaluation compared with other haplotype groups and would quite likely be the non-remitter to 8-week antidepressant treatment (P=0.006). Our findings show, for the first time, that GSK3B genetic variants play a role in the SSRI antidepressant therapeutic response and support the hypothesis that drugs regulating GSK3B activity may represent a novel treatment strategy for MDD.The Pharmacogenomics Journal (2008) 8, 384–390; doi:10.1038/sj.tpj.6500486; published online 15 January 2008 [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
126. Amygdala volume in major depressive disorder: a meta-analysis of magnetic resonance imaging studies.
- Author
-
Hamilton, J P, Siemer, M, and Gotlib, I H
- Subjects
MENTAL depression ,DEPRESSED persons ,PEOPLE with mental illness ,MENTAL health ,AMYGDALOID body - Abstract
Major depressive disorder has been associated with volumetric abnormality in the amygdala. In this meta-analysis we examine results from magnetic resonance imaging volumetry studies of the amygdala in depression in order to assess both the nature of the relationship between depression and amygdala volume as well as the influence of extraexperimental factors that may account for significant variability in reported findings. We searched PubMed and ISI Web of Knowledge databases for articles published from 1985 to 2008 that used the wildcard terms ‘Depress
* ’ and ‘Amygdal* ’ in the title, keywords or abstract. From the 13 studies that met inclusion criteria for our meta-analysis, we calculated aggregate effect size and heterogeneity estimates from amygdala volumetric data; we then used meta-regression to determine whether variability in specific extraexperimental factors accounted for variability in findings. The lack of a reliable difference in amygdala volume between depressed and never-depressed individuals was accounted for by a positive correlation between amygdala volume differences and the proportion of medicated depressed persons in study samples: whereas the aggregate effect size calculated from studies that included only medicated individuals indicated that amygdala volume was significantly increased in depressed relative to healthy persons, studies with only unmedicated depressed individuals showed a reliable decrease in amygdala volume in depression. These findings are consistent with a formulation in which an antidepressant-mediated increase in levels of brain-derived neurotrophic factor promotes neurogenesis and protects against glucocorticoid toxicity in the amygdala in medicated but not in unmedicated depression.Molecular Psychiatry (2008) 13, 993–1000; doi:10.1038/mp.2008.57; published online 27 May 2008 [ABSTRACT FROM AUTHOR]- Published
- 2008
- Full Text
- View/download PDF
127. Contents of general practitioner-patient consultations in the treatment of depression.
- Author
-
Linden, Michael, Christof, Tatjana, and Rentzsch, Christiane
- Subjects
COUNSELING ,THERAPEUTICS ,MENTAL depression ,ANTIDEPRESSANTS ,PATIENTS ,DEPRESSED persons ,DRUG therapy - Abstract
Background: Counseling of patients is an indispensable part of any drug treatment and even more so in the treatment of depression.Objective: To describe the content of counseling additional to prescribing an antidepressant drug.Setting: Sixty-three general practices from all over Germany.Patients: Three hundred two patients with the diagnosis of either a depressive episode or a recurrent depressive disorder.Measurements: Assessment of the content of the physician-patient encounter by content analysis following the pivotal topic method.Design: Qualitative study embedded in a drug utilization study on mirtazapine.Results: In the initial sessions general practitioners focused on building a good therapeutic alliance, assessing the symptoms of illness, explaining the course of treatment, assuring medication compliance, and discussing problems of life. In the middle phase of treatment, physicians also dealt with building a therapeutic alliance, medication compliance, and the progress and course of illness. In the last phase relapse prevention was an important topic. Psychological topics were more important than medication topics. Almost no importance was given to management of side effects, change of cognitions, or suicidal tendencies.Limitations: No information is available on how content was actually discussed. Only encounters were observed where an antidepressant was prescribed.Conclusions: Counseling plays an important part in day-to-day encounters of general practitioners. Pharmacotherapy is embedded in comprehensive psychological care. Training programs for general practitioners should be specific in respect to different tasks and parts of the physician-patient encounter (e.g., building a therapeutic alliance, support for life problems or change of cognitions). [ABSTRACT FROM AUTHOR]- Published
- 2008
- Full Text
- View/download PDF
128. DETA/NONOate, a nitric oxide donor, produces antidepressant effects by promoting hippocampal neurogenesis.
- Author
-
Hua, Yao, Huang, Xin-Yan, Zhou, Li, Zhou, Qi-Gang, Hu, Yao, Luo, Chun-Xia, Li, Fei, and Zhu, Dong-Ya
- Subjects
NITRIC oxide ,DEVELOPMENTAL neurobiology ,ANTIDEPRESSANTS ,HIPPOCAMPUS (Brain) - Abstract
Increasing evidence suggests that depression may be associated with a lack of hippocampal neurogenesis. Our recent study shows that endogenous nitric oxide (NO) contributes to chronic mild stress (CMS)-induced depression by suppressing hippocampal neurogenesis. The aim of this study was to investigate the effects of exogenous NO in CMS-induced depression in young adult mice. In normal mice, administration of a pure NO donor ( Z)-1-[ N-(2-aminoethyl)- N-(2-ammonioethyl) aminio] diazen-1-ium-1,2-diolate (DETA/NONOate; 0.4 mg/kg, i.p., for 7 days) produced an antidepressant-like effect and significantly increased hippocampal neurogenesis. The mice exposed to CMS exhibited behavioral changes typical of depression and impaired neurogenesis in the hippocampus. Treatment with DETA/NONOate (0.4 mg/kg, i.p., for 7 days) reversed CMS-induced behavioral despair and hippocampal neurogenesis impairment. We treated mice with a telomerase inhibitor 3′-azido-deoxythymidine (AZT; 100 mg/kg, i.p., for 14 days) to disrupt neurogenesis. From day 4 to day 11 of AZT treatment, mice were injected with DETA/NONOate (0.4 mg/kg, i.p., for 7 days). Disrupting hippocampal neurogenesis blocked the antidepressant effect of DETA/NONOate. Our findings suggest that exogenous NO benefits chronic stress-induced depression by stimulating hippocampal neurogenesis and may represent a novel approach for the treatment of depressive disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
129. S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models.
- Author
-
Dekeyne, Anne, Mannoury la Cour, Clotilde, Gobert, Alain, Brocco, Mauricette, Lejeune, Françoise, Serres, Florence, Sharp, Trevor, Daszuta, Annie, Soumier, Amélie, Papp, Mariusz, Rivet, Jean-Michel, Flik, Gunnar, Cremers, Thomas, Muller, Olivier, Lavielle, Gilbert, and Millan, Mark
- Subjects
PSYCHOPHARMACOLOGICAL research ,ANTIDEPRESSANTS ,SEROTONIN ,LOCUS coeruleus - Abstract
Serotonin (5-HT)
2C receptors are implicated in the control of mood, and their blockade is of potential interest for the management of anxiodepressive states. Herein, we characterized the in vitro and in vivo pharmacological profile of the novel benzourea derivative, S32006. Standard cellular, electrophysiological, neurochemical, and behavioral procedures were used. S32006 displayed high affinity for human (h)5-HT2C and h5-HT2B receptors (p Ki s, 8.4 and 8.0, respectively). By contrast, it had negligible (100-fold lower) affinity for h5-HT2A receptors and all other sites examined. In measures of Gq-protein coupling/phospholipase C activation, S32006 displayed potent antagonist properties at h5-HT2C receptors (p KB values, 8.8/8.2) and h5-HT2B receptors (7.8/7.7). In vivo, S32006 dose-dependently (2.5–40.0 mg/kg, i.p. and p.o.) abolished the induction of penile erections and a discriminative stimulus by the 5-HT2C receptor agonist, Ro60,0175, in rats. It elevated dialysis levels of noradrenaline and dopamine in the frontal cortex of freely moving rats, and accelerated the firing rate of ventrotegmental dopaminergic and locus ceruleus adrenergic neurons. At similar doses, S32006 decreased immobility in a forced-swim test in rats, reduced the motor depression elicited by 5-HT2C and α2 -adrenoceptor agonists, and inhibited both aggressive and marble-burying behavior in mice. Supporting antidepressant properties, chronic (2–5 weeks) administration of S32006 suppressed “anhedonia” in a chronic mild stress procedure and increased both expression of BDNF and cell proliferation in rat dentate gyrus. Finally, S32006 (0.63–40 mg/kg, i.p. and p.o) displayed anxiolytic properties in Vogel conflict and social interaction tests in rats. S32006 is a potent 5-HT2C receptor antagonist, and possesses antidepressant and anxiolytic properties in diverse rodent models. [ABSTRACT FROM AUTHOR]- Published
- 2008
- Full Text
- View/download PDF
130. Maintenance Treatment with Fluoxetine is Necessary to Sustain Normal Levels of Synaptic Markers in an Experimental Model of Depression: Correlation with Behavioral Response.
- Author
-
Reinés, Analía, Cereseto, Marina, Ferrero, Alejandro, Sifonios, Laura, Podestá, Maria Fernanda, and Wikinski, Silvia
- Subjects
FLUOXETINE ,PHARMACODYNAMICS ,SYNAPSES ,MENTAL depression ,DEPRESSED persons ,PATHOLOGICAL physiology ,ANTIDEPRESSANTS ,IMMUNOHISTOCHEMISTRY - Abstract
Dysfunction of hippocampal plasticity has been proposed to play a critical role in the pathophysiology of depression. However, antidepressant drug effects on synaptic plasticity and cytoskeletal remodeling remain controversial. The aim of the present study was to evaluate in animals exposed to the learned helplessness (LH) paradigm, an accepted experimental model of depression, the effect of chronic treatment with fluoxetine (FLX) on synaptic and cytoskeletal proteins known to undergo plastic changes. Synaptophysin (SYN), postsynaptic density 95 (PSD-95), axon growth-associated protein 43 (GAP-43), and cytoskeletal proteins (intermediate neurofilaments and MAP-2) were studied in the hippocampus by immunohistochemistry. Whereas LH animals treated 21 days with saline (LH-S group) displayed diminished SYN and PSD-95 immunostainings in the CA3 but not in the DG, chronic treatment with FLX not only reversed the despaired behavior induced by exposure to LH paradigm, but also fully recovered SYN and PSD-95 labeling to control values. Similar results were obtained for the axonal remodeling marker GAP-43. FLX treatment did not modify either the decreased light neurofilament subunit (NFL) observed in the hippocampus of LH animals or any other cytoskeletal protein studied. When FLX treatment was withdrawn for 90 days in those LH-FLX animals in which reversion of despair had been observed at day 25, recurrence of despaired behavior was found accompanied by decreased SYN, PSD-95, and NFL labelings. Results indicate that the synapse remodeling induced by FLX in the CA3 region could underlie its behavioral efficacy despite the absence of cytoskeletal remodeling and that the stability of synaptic changes would depend on the continuous administration of the drug.Neuropsychopharmacology (2008) 33, 1896–1908; doi:10.1038/sj.npp.1301596; published online 17 October 2007 [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
131. Lack of persistent effects of ketamine in rodent models of depression.
- Author
-
Popik, Piotr, Kos, Tomasz, Sowa-Kućma, Magdalena, and Nowak, Gabriel
- Subjects
KETAMINE ,MENTAL depression ,NEUROCHEMISTRY ,ANTIDEPRESSANTS ,ADRENERGIC receptors - Abstract
We investigated the immediate and enduring effects of ketamine in behavioral and neurochemical assays predictive of antidepressant activity. One week after a single administration of ketamine (50–160 mg/kg), otherwise experimentally naive rats and mice were tested either in the forced swim test (FST) or the tail suspension test (TST). Other mice were also tested twice in the FST: immediately and 2 weeks after a single dose (1.25–50 mg/kg) of ketamine. In the next series of experiments, rats treated for 2 weeks twice daily with ketamine (50 or 160 mg/kg) or desipramine (10 mg/kg) were challenged with apomorphine and scored for locomotor activity and assayed for the density of cortical beta-adrenoceptors. The latter test was also carried out in rats that had received a single dose of ketamine (50 mg/kg) 1 week before the assay. The antidepressant-like (FST) and locomotor effects of ketamine (50 mg/kg) and desipramine (10 mg/kg) were assessed after their chronic (2 weeks, twice daily) administration as well. We report the lack of enduring antidepressant-like effect of ketamine in both rats and mice. A 2-week treatment with ketamine neither changed apomorphine-evoked locomotor hyperactivity nor did it decrease the density of cortical beta-adrenoceptors. However, some tolerance to the antidepressant-like effect of ketamine was noted in the FST, but it was accompanied by sensitization to its locomotor stimulatory effects. These data indicate that ketamine neither produces enduring antidepressant-like effects in rodents nor does it display antidepressant-like behavioral or neurochemical effects after chronic treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
132. Treating Depressed Children With Antidepressants: More Harm than Benefit?
- Author
-
Antonuccio, David
- Subjects
TREATMENT of depression in children ,ANTIDEPRESSANTS ,PEDIATRIC pharmacology ,MENTAL health of youth ,YOUTH & drugs - Abstract
Since the FDA held hearings in February 2004 on the safety of antidepressants in children, there has been a great deal of controversy regarding the use of antidepressants in children, culminating in the well publicized black box warnings about increased risk of suicidal behavior in children and young adults (up to age 25) caused by these medications. Using questions that a parent might ask, the current article attempts to summarize the efficacy and safety data on the use of antidepressants in children so that psychologists, with or without prescription privileges, may be able to inform parents of young patients about the science behind this treatment. This article is based on a presentation at the 2007 American Psychological Association conference by the author in acceptance of the 2006 APAHC Bud Orgel Award for Distinguished Achievement in Research. Much of the information described in this article is drawn from the recent APA Report of the Working Group on Psychoactive Medications for Children and Adolescents. (Brown et al. 2006; available at ) culminating in a book by the same authors (Brown et al., Childhood mental health disorders: Evidence base and contextual factors for psychosocial, psychopharmacological, and combined interventions ). [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
133. Effects of chronic treatment with citalopram on cannabinoid and opioid receptor-mediated G-protein coupling in discrete rat brain regions.
- Author
-
Hesketh, Shirley A., Brennan, Adrian K., Jessop, David S., and Finn, David P.
- Subjects
CANNABINOIDS ,CANNABIS (Genus) ,HALLUCINOGENIC drugs ,OPIOID receptors ,DRUG receptors ,G proteins - Abstract
There is growing interest in investigating the mechanisms of action of selective serotonin reuptake inhibitors (SSRIs), beyond their association with the serotonergic system, due to their wide therapeutic potential for disorders including depression, pain and addiction. The aim of this study was to investigate whether chronic treatment with the SSRI, citalopram, alters the functional coupling of G
i/o -associated cannabinoid type 1 (CB1 ) and μ-opioid receptors in selected areas of rat brain implicated in psychiatric disorders and pain. Using an autoradiographic approach, the effects of the cannabinoid receptor agonist, HU210 (in the presence or absence of the CB1 receptor antagonist AM251), or the μ-opioid receptor agonist, [ d-Ala2 , N–Me–Phe4,Gly5 -ol]-enkephalin (DAMGO; in the presence or absence of the μ-opioid receptor antagonist d-Phe–Cys–Tyr- d-Trp–Orn–Thr–Pen–Thr–NH2 ), on [35 S]GTPγS binding in discrete brain regions of citalopram-treated (10 mg kg−1 day−1 for 14 days by subcutaneous minipump) and control rats were investigated. The HU210-induced increase in [35 S]GTPγS binding observed in the hypothalamic paraventricular nucleus of control rats was abolished after chronic treatment with citalopram. Reduced response to HU210 in rats receiving chronic treatment with citalopram was also observed in the hippocampus and medial geniculate nucleus. Citalopram had no significant effect on DAMGO-induced [35 S]GTPγS binding in the brain regions investigated, with the exception of the medial geniculate nucleus where a modest impairment was observed. These data provide evidence for reduced cannabinoid receptor-mediated G-protein coupling in the hypothalamus, hippocampus and medial geniculate nucleus of rats chronically treated with citalopram, effects which may, in part, underlie the mechanism of action of SSRIs. [ABSTRACT FROM AUTHOR]- Published
- 2008
- Full Text
- View/download PDF
134. Selective Serotonin Reuptake Inhibitors and Other Antidepressants and Risk of Fracture.
- Author
-
Vestergaard, Peter, Rejnmark, Lars, and Mosekilde, Leif
- Subjects
SEROTONIN uptake inhibitors ,ANTIDEPRESSANTS ,BONE fractures ,MONOAMINE oxidase ,MEDICAL research - Abstract
Our aim was to study fracture risk in users of various antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, and the group of other antidepressants including monoamine oxidase B inhibitors and drugs with effect on the norepinephrine system) and its relationship with effects on inhibition of the cholinergic and serotonin transporter system. We conducted a case-control study with 124,655 fracture cases and 373,962 age- and gender-matched controls. The exposure was use of antidepressants and a number of confounders. Among the tricyclic antidepressants, amitriptyline and clomipramine were associated with a dose-dependent increase in fracture risk, while imipramine and nortriptyline were not. Amityriptyline was associated with an increased risk of fractures at low doses, while the other tricyclic antidepressants were not. Among the selective serotonin reuptake inhibitors, citalopram, fluoxetine, and sertraline were associated with a dose-dependent increase in fracture risk, while the increase was borderline statistically insignificant for paroxetine. The group of other antidepressants was not associated with fracture risk. The increase in fracture risk was significantly associated with the pharmacodynamic effect on the serotonin transporter system but not on other signaling systems. The effect of antidepressants on the risk of fractures may be linked to their effect on the serotonin transporter system. While selective serotonin receptor uptake inhibitors were associated with an increased fracture risk, tricyclic antidepressants and the group of other antidepressants were not systematically associated with fracture risk. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
135. Behavioral Effects of Chronic Fluoxetine in BALB/cJ Mice Do Not Require Adult Hippocampal Neurogenesis or the Serotonin 1A Receptor.
- Author
-
Holick, Kerri A., Lee, Daniel C., Hen, René, and Dulawa, Stephanie C.
- Subjects
FLUOXETINE ,DEVELOPMENTAL neurobiology ,SEROTONIN ,ANTIDEPRESSANTS ,NEURONS - Abstract
We previously reported that chronic, but not subchronic, treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine altered behavior in the forced swimming test (FST) in BALB/cJ mice. We now use this model to investigate mechanisms underlying the delayed onset of the behavioral response to antidepressants, specifically (1) adult hippocampal neurogenesis and (2) expression of the 5-HT1A receptor. Here, we show data validating this model of chronic antidepressant action. We found the FST to be selectively responsive to chronic administration of the SSRI fluoxetine (18 mg/kg/day) and the tricyclic antidepressant desipramine (20 mg/kg/day), but not to the antipsychotic haloperidol (1 mg/kg/day) in BALB/cJ mice. The behavioral effects of fluoxetine emerged by 12 days of treatment, and were affected neither by ablation of progenitor cells of the hippocampus nor by genetic deletion of the 5-HT1A receptor. The effect of fluoxetine in the BALB/cJ mice was also neurogenesis-independent in the novelty-induced hypophagia test. We also found that chronic fluoxetine does not induce an increase in cell proliferation or the number of young neurons as measured by BrdU and doublecortin immunolabeling, respectively, in BALB/cJ mice. These data are in contrast to our previous report using a different strain of mice (129SvEvTac). In conclusion, we find that BALB/cJ mice show a robust response to chronic SSRI treatment in the FST, which is not mediated by an increase in new neurons in the hippocampus, and does not require the 5-HT1A receptor. These findings suggest that SSRIs can produce antidepressant-like effects via distinct mechanisms in different mouse strains.Neuropsychopharmacology (2008) 33, 406–417; doi:10.1038/sj.npp.1301399; published online 11 April 2007 [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
136. The Antidepressant Desipramine Requires the ABCB1 (Mdr1)-Type p-Glycoprotein to Upregulate the Glucocorticoid Receptor in Mice.
- Author
-
Yau, Joyce L. W., Noble, June, Thomas, Sarah, Kerwin, Robert, Morgan, Phillip E., Lightman, Stafford, Seckl, Jonathan R., and Pariante, Carmine M.
- Subjects
ANTIDEPRESSANTS ,GLYCOPROTEINS ,GLUCOCORTICOID receptors ,ANIMAL models in research ,HYPOTHALAMIC-pituitary-adrenal axis ,MULTIDRUG resistance ,CELL culture ,MESSENGER RNA - Abstract
The mechanisms by which antidepressants regulate the hypothalamic-pituitary-adrenal (HPA) axis are still unknown. The ABCB1-type multiple drug resistance (MDR) p-glycoprotein (PGP) regulates the HPA axis by limiting the access of glucocorticoids to the brain in mice and humans. Previous work in cell cultures has found that antidepressants enhance glucocorticoid receptor (GR) function in vitro by inhibiting MDR PGP, and therefore by increasing the intracellular concentration of glucocorticoids—but this model has never been tested directly in animals. Here, the tricyclic antidepressant, desipramine (20 mg/kg/day, i.p., for seven days), was administered to abcb1ab MDR PGP knockout mice (congenic on the FVB/N background strain) and to FVB/N controls. The hippocampal mRNA expression of GR, mineralocorticoid receptor (MR), MDR (Mdr1a) PGP, and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) were measured, together with plasma corticosterone levels. In FVB/N controls, desipramine induced a significant upregulation of GR mRNA in the CA1 region (+31%; p=0.045); in contrast, in abcb1ab (−/−) mice, desipramine induced a significant downregulation of GR mRNA in the CA1 region (−45%; p=0.004). MR mRNA expression was unaltered. Desipramine decreased corticosterone levels in both FVB/N controls and in abcb1ab (−/−) mice, but in abcb1ab (−/−) mice the effects were smaller. Specifically, in FVB/N controls (but not in abcb1ab (−/−) mice), desipramine reduced corticosterone levels not only compared with saline-treated mice but also compared with the ‘physiological’ levels of untreated mice (−39%; p=0.05). Finally, desipramine reduced Mdr1a mRNA expression across all hippocampus areas (−9 to −23%), but had no effect on 11β-HSD1 mRNA expression. These data support the notion that the MDR PGP is one of the molecular targets through which antidepressants regulate the HPA axis.Neuropsychopharmacology (2007) 32, 2520–2529; doi:10.1038/sj.npp.1301389; published online 14 March 2007 [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
137. The efficacy of the combination of sertraline with buspirone for smoking cessation.
- Author
-
Carrão, Jorge Luiz, Moreira, Leila Beltrami, and Fuchs, Flávio Danni
- Published
- 2007
- Full Text
- View/download PDF
138. Antidepressant-like effects of the novel, selective, 5-HT2C receptor agonist WAY-163909 in rodents.
- Author
-
Rosenzweig-Lipson, Sharon, Sabb, Annmarie, Stack, Gary, Mitchell, Paul, Lucki, Irwin, Malberg, Jessica E., Grauer, Steve, Brennan, Julie, Cryan, John F., Rizzo, Stacey J. Sukoff, Dunlop, John, Barrett, James E., and Marquis, Karen L.
- Subjects
ANTIDEPRESSANTS ,MENTAL depression ,AGGRESSION (Psychology) ,ANIMAL models in research ,RATS - Abstract
Activation of one or more of the serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of SSRIs. The present studies were conducted to evaluate the effects of the novel 5-HT
2C receptor agonist WAY-163909 in animal models of antidepressant activity (forced swim test (FST), resident–intruder, olfactory bulbectomy (BULB)), in a schedule-induced polydipsia (SIP) model of obsessive–compulsive disorder and in a model for evaluating sexual dysfunction. WAY-163909 (10 mg/kg, i.p. or s.c.) decreased immobility time in Wistar–Kyoto rats in the FST, effects that were reversed by the 5-HT2C/2B receptor antagonist SB 206553. Moreover, in Sprague-Dawley rats, the profile of WAY-163909 (decreased immobility, increased swimming) in the FST was comparable to the effects of SSRIs. Acute treatment with WAY-163909 (0.33 mg/kg, s.c.) decreased rodent aggression at doses lower than those required for decreasing total behavior. Administration of WAY-163909 (3 mg/kg, i.p.) for 5 or 21 days decreased the BULB-induced hyperactivity in rats. Additionally, acute administration of WAY-163909 (3 mg/kg, i.p.) decreased adjunctive drinking in a SIP model. The effects of WAY-163909 were reversed by the 5-HT2C/2B receptor antagonist SB 206553 and the selective 5-HT2C receptor antagonist SB 242084. Chronic administration of WAY-163909 produced deficits in sexual function at doses higher (10 mg/kg, i.p.) than those required for antidepressant-like effects in the BULB model. Taken together, these results demonstrate that the novel 5-HT2C receptor agonist WAY-163909 produces rapid onset antidepressant-like effects in animal models and may be a novel treatment for depression. [ABSTRACT FROM AUTHOR]- Published
- 2007
- Full Text
- View/download PDF
139. Evaluation of fatty acid amide hydrolase inhibition in murine models of emotionality.
- Author
-
Naidu, Pattipati S., Varvel, Stephen A., Ahn, Kyunghye, Cravatt, Benjamin F., Martin, Billy R., and Lichtman, Aron H.
- Subjects
FATTY acids ,HYDROLASES ,ANTIDEPRESSANTS ,MENTAL depression ,ANXIETY ,CANNABINOIDS - Abstract
Manipulations of the endocannabinoid/fatty acid amide hydrolase (FAAH) signaling systems result in conflicting and paradoxical effects in rodent models of emotional reactivity. In the present study, we tested the hypothesis that the inhibition of FAAH would elicit significant effects in murine models used to screen anxiolytic and antidepressant drugs. FAAH (−/−) mice and wild-type mice treated with FAAH inhibitors (URB597 and OL-135) were evaluated in standard behavioral screening models for antidepressant (i.e., tail suspension and forced-swim tests) and anxiolytic (i.e., elevated plus maze) agents. The doses of URB597 and OL-135 selected were based on their ability to augment the pharmacological effects (i.e., analgesia, catalepsy, and hypothermia) of exogenously administered anandamide. FAAH (−/−) mice, anandamide-injected FAAH (−/−) mice, or wild-type mice injected with FAAH inhibitors or anandamide failed to exhibit significant effects in standard tests of emotional reactivity, although the antidepressant desipramine and the anxiolytic agent midazolam were active in the appropriate assays. FAAH- (−/−) and URB597-treated mice finally displayed significant effects in the tail suspension test when substantial methodological changes were made (i.e., altered ambient light and increased sample sizes). Although FAAH suppression can elicit significant effects under some instances in which consequential procedural modifications are made, the present results indicate that the pharmacological inhibition or genetic deletion of FAAH is ineffective in standard mouse models of emotional reactivity. It remains to be established whether the effects of FAAH inhibition in these modified tasks are predictive of their efficacy in treating emotional disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
140. Effects of acute and chronic antidepressant treatments on memory performance: a comparison between paroxetine and imipramine.
- Author
-
Naudon, Laurent, Hotte, Maïté, and Jay, Thérèse M.
- Subjects
ANTIDEPRESSANTS ,SIDE effects of imipramine ,DRUG side effects ,SEROTONIN uptake inhibitors ,SHORT-term memory ,COGNITIVE ability - Abstract
The cognitive impairments apparent in many depressed patients appear to be alleviated by chronic treatments with antidepressants. However, evaluation of antidepressant treatments in rodents rarely includes investigation of their effects on cognitive performance. The aim of this study was to investigate in rat the effects of paroxetine, a selective serotonin reuptake inhibitor antidepressant, and imipramine, a tricyclic antidepressant, on learning and memory in spatial and non-spatial tasks. Adult male Sprague–Dawley rats weighing 230–250 g were used in two sets of experiments. Spatial working memory was first tested in a radial-arm maze using the delayed spatial win-shift task. During the course of a 10-day treatment, paroxetine-treated rats (10 mg/kg) did not show any deficit in memory performance. Conversely, imipramine-treated rats (10 mg/kg) made significantly more errors than controls. Secondly, we tested temporal order memory for objects. Rats received one injection or chronic injections (28 days) of imipramine (10 mg/kg), paroxetine (10 mg/kg) or saline. In contrast to controls, on the day after the acute injection, both imipramine- and paroxetine-treated rats were unable to discriminate the old from the recent objects. After chronic treatment, the imipramine-treated rats were unable to differentiate between the two objects, whereas paroxetine-treated rats, as controls, spent more time exploring the old one. When the delay before the test phase was increased to 4 h, controls could not discriminate the objects, whereas rats treated for 28 days with paroxetine were able to distinguish the old from the recent object. In contrast to the persistent harmful effects of imipramine, chronic treatment with paroxetine does not alter spatial working memory performance and appears to improve temporal order memory performance. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
141. The pharmacological management of childhood anxiety disorders: a review.
- Author
-
Reinblatt, Shauna P. and Riddle, Mark A.
- Subjects
ANXIETY disorders ,ANXIETY in children ,PEDIATRIC pharmacology ,ANTIDEPRESSANTS ,PSYCHOPHARMACOLOGY - Abstract
Pediatric anxiety is a prevalent psychiatric disorder that may have important implications for school, social, and academic function. Psychopharmacological approaches to the treatment of pediatric anxiety have expanded over the past 20 years and increasing empirical evidence helps guide current clinical practice. To review studies which examine the pharmacological treatment of pediatric anxiety disorders, including obsessive–compulsive disorder and to summarize treatment implications. All relevant studies were searched using MEDLINE and PsycINFO search engines, supplemented by a manual bibliographical search; studies published between 1985 and 2006 that met inclusion criteria were examined. This article provides a systematic review of the psychopharmacological treatment of pediatric anxiety disorders based on available empirical evidence, with a focus on randomized controlled trials. General treatment principles and pharmacological management of specific pediatric anxiety disorders are also reviewed. There is good evidence to support the efficacy of several pharmacological agents including the selective serotonin reuptake inhibitors to treat pediatric anxiety and obsessive–compulsive disorder, although there are still many unanswered questions. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
142. Evaluation of reward processes in an animal model of depression.
- Author
-
Slattery, David A., Markou, Athina, and Cryan, John F.
- Subjects
ANHEDONIA ,MENTAL depression ,NEURAL circuitry ,DRUGS of abuse ,REWARD (Psychology) ,ANTIDEPRESSANTS ,LABORATORY animals - Abstract
Anhedonia is a core symptom of major depression. Deficits in reward function, which underlie anhedonia, can be readily assessed in animals. Therefore, anhedonia may serve as an endophenotype for understanding the neural circuitry and molecular pathways underlying depression. Surprisingly, there is scant knowledge regarding alterations in brain reward function after olfactory bulbectomy (OB), an animal model which results in a behavioural syndrome responsive to chronic antidepressant treatment. Therefore, the present studies aimed to assess reward function after bulbectomy. The present study utilized sucrose preference, cocaine-induced hyperlocomotion and intra-cranial self-stimulation (ICSS) responding to examine reward processes in the OB model. Bulbectomized animals showed a marked preference (>90%) for 0.8% sucrose solution compared with water; similar to the preference exhibited by sham controls. Importantly, there were pronounced deficits in brain reward function, as assessed using ICSS, which lasted 8 days before returning to baseline levels. Furthermore, bulbectomized animals were hyper-responsive to the locomotor stimulating properties of an acute and a repeated cocaine regimen. However, no difference in ICSS facilitation was observed in response to an acute cocaine injection. Taken together, these results suggest that bulbectomized rats display alterations in brain reward function, but these changes are not long-lasting and thus, not amenable to investigating the effects of pharmacological interventions. However, given that OB animals are hypersensitive to drugs of abuse, bulbectomy may be an appropriate inducing factor for the development of animal models of co-morbid depression and drug dependence. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
143. The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not β2- or α7-nicotinic acetylcholine receptor subunit knockout mice.
- Author
-
Rabenstein, R. L., Caldarone, B. J., and Picciotto, M. R.
- Subjects
MENTAL depression ,ANIMAL models in research ,NICOTINE ,ANTIDEPRESSANTS ,MECAMYLAMINE ,MUSCULOSKELETAL system - Abstract
Increases in cholinergic transmission are linked to depression in human subjects and animal models. We therefore examined the effect of decreasing nicotinic acetylcholine receptor (nAChR) activity in tests of antidepressant efficacy using C57BL/6J mice. We determined whether the noncompetitive nAChR antagonist mecamylamine had antidepressant-like effects in the forced swim test (FST) and tail suspension test (TST). These experiments were repeated in mice lacking either the β2- or α7-nAChR subunits to identify the nAChR subunits involved in mediating the antidepressant response to mecamylamine. Adult mice on the C57BL/6J background were acutely administered mecamylamine i.p. 30 min before testing in the FST or TST. A dose–response study showed that mecamylamine significantly decreased immobility time in the TST at the 1.0-mg/kg dose but did not alter baseline locomotor activity. The competitive nAChR antagonist dihydro-β-erythroidine, but not the blood–brain barrier impermeant antagonist hexamethonium, also decreased immobility in the TST. One milligram per kilogram of mecamylamine also significantly decreased time immobile in the FST whereas both β2- and α7-knockout mice were insensitive to the effects of mecamylamine in the FST. Decreased activity of central nAChRs has antidepressant-like effects in both the TST and FST and these effects are dependent on both β2 and α7 subunits. Therefore, compounds that decrease nAChR activity may be attractive new candidates for development as antidepressants in humans. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
144. The Effects of Chronic Norepinephrine Transporter Inactivation on Seizure Susceptibility in Mice.
- Author
-
Ahern, Todd H., Javors, Martin A., Eagles, Douglas A., Martillotti, Jared, Mitchell, Heather A., Liles, Larry Cameron, and Weinshenker, David
- Subjects
EPILEPSY ,DEPRESSED persons ,MENTAL depression ,ANTIDEPRESSANTS ,ANTICONVULSANTS ,MICE - Abstract
Epilepsy and depression are comorbid disorders, but the mechanisms underlying their relationship have not been identified. Traditionally, many antidepressants have been thought to increase seizure incidence, although this remains controversial, and it is unclear which medications should be used to treat individuals suffering from both epilepsy and depression. Since the neurotransmitter norepinephrine (NE) has both antidepressant and anticonvulsant properties, we speculated that NE transporter (NET) inhibitor antidepressants might be therapeutic candidates for comorbid individuals. To test this idea, we assessed the effects of chronic administration (via osmotic minipump) of the selective NET inhibitor reboxetine on flurothyl-induced seizures in mice. We found that reboxetine had both proconvulsant and anticonvulsant properties; it lowered both seizure threshold and maximal seizure severity. NET knockout (NET KO) mice essentially phenocopied the effects of reboxetine on flurothyl-induced seizures, and the trends were extended to pentylenetetrazole and maximal electroshock seizures (MES). Furthermore, reboxetine had no further effect in NET KO mice, demonstrating the specificity of reboxetine for the NET. We next tested the chronic and acute effects of other classes of antidepressants (desipramine, imipramine, sertraline, bupropion, and venlafaxine) on seizure susceptibility. Only venlafaxine was devoid of proconvulsant activity, and retained some anticonvulsant activity. These results suggest that chronic antidepressant drug treatment has both proconvulsant and anticonvulsant effects, and that venlafaxine is a good candidate for the treatment of epilepsy and depression comorbidity.Neuropsychopharmacology (2006) 31, 730–738. doi:10.1038/sj.npp.1300847; published online 27 July 2005 [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
145. A Comparison of Brain Serum Pharmacokinetics of R-Fluoxetine and Racemic Fluoxetine: A 16-F MRS Study.
- Author
-
Henry, Michael E., Schmidt, Mark E., Hennen, John, Villafuerte, Rosemond A., Butman, Michelle L., Tran, Pierre, Kerner, Lynn T., Cohen, Bruce, and Renshaw, Perry F.
- Subjects
ANTIDEPRESSANTS ,DRUG development ,ENANTIOMERS ,FLUORINE ,MAGNETIC resonance imaging ,FLUOXETINE ,PHARMACOKINETICS - Abstract
Racemic fluoxetine consists of R- and S-fluoxetine, which are metabolized to R and S norfluoxetine, respectively. This study was designed to compare brain levels achieved with R-fluoxetine to those achieved with racemic fluoxetine in healthy subjects using fluorine-19 (19-F) magnetic resonance spectroscopy (MRS). In all, 13 healthy volunteers received study drug for 5 weeks using a dosing schedule designed to achieve steady state for 20 mg/day racemic fluoxetine, 80 mg/day R-fluoxetine, or 120 mg/day R-fluoxetine. The resulting brain drug levels were measured using 19-F MRS. At 5 weeks, the racemate, 80 and 120 mg/day R-fluoxetine groups had mean brain levels of 25.5, 34.9, and 41.4 μM, respectively. In the serum, R-norfluoxetine, which is thought to be an inactive metabolite, accounted for 17, 71, and 63% of the fluoxetine/norfluoxetine concentration, respectively. When the relative proportion of active to total species in serum are taken into account, the data suggest that doses of R-fluoxetine greater than 120 mg/day would be needed to achieve brain levels of active drug comparable to 20 mg/day of racemate. The 120 mg/day R-fluoxetine group experienced a mean increase in QTc interval of 44 ms, with one individual having an increase of 89 ms, which suggests that higher doses may not be tolerable. While these data support the use of MRS to aid in defining the therapeutic dose range for drug development, they also highlight the need for additional studies with concurrent animal models to establish the validity of using serum drug/metabolite ratios to interpret MRS determined brain drug levels. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
146. Selective Phosphorylation of Nuclear CREB by Fluoxetine is Linked to Activation of CaM Kinase IV and MAP Kinase Cascades.
- Author
-
Tiraboschi, Ettore, Tardito, Daniela, Kasahara, Jiro, Moraschi, Stefania, Pruneri, Paolo, Gennarelli, Massimo, Racagni, Giorgio, and Popoli, Maurizio
- Subjects
ANTIDEPRESSANTS ,PSYCHIATRIC drugs ,MENTAL depression ,CARRIER proteins ,CYCLIC adenylic acid ,FLUOXETINE ,SEROTONIN uptake inhibitors ,PROTEIN kinases - Abstract
Regulation of gene expression is purported as a major component in the long-term action of antidepressants. The transcription factor cAMP-response element-binding protein (CREB) is activated by chronic antidepressant treatments, although a number of studies reported different effects on CREB, depending on drug types used and brain areas investigated. Furthermore, lithe is known as to what signaling cascades are responsible for CREB activation, although cAMP-protein kinase A (PICA) cascade was suggested to be a central player. We investigated how different drugs (fluoxetine (FLX), desipramine (DMI), reboxetine (RBX)) affect CREB expression and phosphorylation of Ser
133 in the hippocampus and prefrontal/frontal cortex (PFCX). Acute treatments did not induce changes in these mechanisms. Chronic FLX increased nuclear phospho-CREB (pCREB) far more markedly than pronoradrenergic drugs, particularly in PFCX. We investigated the function of the main signaling cascades that were shown to phosphorylate and regulate CREB. PKA did not seem to account for the selective increase of pCREB induced by FLX. All drug treatments markedly increased the enzymatic activity of nuclear Ca2+ /calmoduIin (CaM) kinase IV (CaMKIV), a major neuronal CREB kinase, in PFCX. Activation of this kinase was due to increased phosphorylation of the activatory residue Thr196 , with no major changes in the expression levels of α- and β-CaM kinase kinase, enzymes that phosphorylate CaMKIV. Again in PFCX, FLX selectively increased the expression level of MAP kinases Erk1/2, without affecting their phosphorylation. Our results show that FLX exerts a more marked effect on CREB phosphorylation and suggest that CaMKIV and MAP kinase cascades are involved in this effect. [ABSTRACT FROM AUTHOR]- Published
- 2004
- Full Text
- View/download PDF
147. Investigation of serotonin-related genes in antidepressant response.
- Author
-
Peters, E. J., Slager, S. L., McGrath, P. J., Knowles, J. A., and Hamilton, S. P.
- Subjects
FLUOXETINE ,SEROTONIN ,ANTIDEPRESSANTS ,GENES ,MENTAL depression ,PHARMACODYNAMICS ,PATIENTS - Abstract
In this study, we sought out to test the hypothesis that genetic factors may influence antidepressant response to fluoxetine. The investigation focused on seven candidate genes in the serotonergic pathway involved in the synthesis, transport, recognition, and degradation of serotonin. Our clinical sample consisted of 96 subjects with unipolar major depression treated with fluoxetine with response variables assessed after a 12-week trial. Patient data were also collected to investigate the pattern of drug response. Using a high-throughput single-nucleotide polymorphism (SNP) genotyping platform and capillary electrophoresis, we genotyped patients at 110 SNPs and four repeat polymorphisms located in seven candidate genes (HTR1A, HTR2A, HTR2C, MAOA, SLC6A4, TPH1, and TPH2). Statistical tests performed included single-locus and haplotype association tests, and linkage disequilibrium (LD) estimation. Little evidence of population stratification was observed in the sample with 20 random SNPs using a genomic control procedure. Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P=0.02-0.04). All odds ratios indicated an increased risk of not responding to fluoxetine. In the specific response vs nonspecific and nonresponse comparison, three SNPs in the TPH2 gene (P=0.02-0.04) were positively associated and one SNP in the HTR2A gene (P=0.02) was negatively associated. When comparing specific response to nonspecific response, we found significant negative associations in three SNPs in the HTR2A gene (P=0.001-0.03) and two SNPs in the MAOA gene (P=0.03-0.05). We observed variable, although strong LD, in each gene and unexpectedly low numbers of estimated haplotypes, formed from tagged SNPs. Significant haplotype associations were found in all but the HTR1A and HTR2C genes. Although these data should be interpreted cautiously due to the small sample size, these results implicate TPH1 and SLC6A4 in general response, and HTR2A, TPH2, and MAOA in the specificity of response to fluoxetine. Intriguingly, we observe that a number of the less frequent alleles of many of the SNP markers were associated with the nonresponse and nonspecific phenotypes.Molecular Psychiatry (2004) 9, 879-889. doi:10.1038/sj.mp.4001502 Published online 30 March 2004 [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
148. Chronic Fluoxetine Treatment Partly Attenuates the Long-Term Anxiety and Depressive Symptoms Induced by MDMA (‘Ecstasy’) in Rats.
- Author
-
Thompson, Murray R., Li, Kong M., Clemens, Kelly J., Gurtman, Clint G., Hunt, Glenn E., Cornish, Jennifer L., and McGregor, Iain S.
- Subjects
ANTIDEPRESSANTS ,ECSTASY (Drug) ,ANXIETY ,MENTAL depression ,SEROTONIN ,FLUOXETINE - Abstract
Use of the drug 3,4-methylenedioxymethamphetamine (MDMA, ’Ecstasy’) can have long-term adverse effects on emotion in both humans and laboratory animals. The present study examined whether chronic treatment with the antidepressant drug fluoxetine could reverse such effects. Male Wistar rats were briefly exposed to MDMA (4 × 5 mg/kg over 4 h) or vehicle on 2 consecutive days. Approximately 9–12 weeks later, half of the rats received a dose of approximately 6 mg/kg/day fluoxetine in their drinking water for a 5week period. Fluoxetine administration reduced fluid intake and body weight in MDMA and vehicle pretreated rats. After several weeks of fluoxetine treatment, rats were assessed on the social interaction test, the emergence test of anxiety and the forced swim model of depression. MDMA pretreated rats showed reduced social interaction, increased anxiety on the .emergence test, and increased immobility and decreased active responses in the forced swim test. Fluoxetine treatment reversed MDMA-induced anxiety in the emergence test and depressive-like effects in the forced swim test, yet exhibited no effects on the social interaction test. MDMA pretreated rats had decreased 5-HT and 5-HIAA levels in limbic and cortical regions, and decreased density of serotonin transporter sites in the cortex. Fluoxetine treatment did not greatly affect 5-HT levels in MDMA pretreated rats, but significantly decreased 5-HIAA levels in all brain sites examined. Postmortem blood serum levels of fluoxetine and norfluoxetine did not differ in MDMA and vehicle pretreated rats. These results indicate that fluoxetine may provide a treatment option for some of the deleterious long-term effects resulting from MDMA exposure. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
149. Comprehensive expression analysis of a rat depression model.
- Author
-
Nakatani, N., Aburatani, H., Nishimura, K., Semba, J., and Yoshikawa, T.
- Subjects
GENE expression ,MENTAL depression ,HIPPOCAMPUS (Brain) ,ANTIDEPRESSANTS ,DEHYDROGENASES - Abstract
Herein we report on a large-scale analysis of gene expression in the 'learned helplessness' (LH) rat model of human depression, using DNA microarrays. We compared gene expression in the frontal cortex (FC) and hippocampus (HPC) of untreated controls, and LH rats treated with saline (LH-S), imipramine or fluoxetine. A total of 34 and 48 transcripts were differentially expressed in the FC and HPC, respectively, between control and LH-S groups. Unexpectedly, only genes for NADH dehydrogenase and zinc transporter were altered in both the FC and HPC, suggesting limited overlap in the molecular processes from specific areas of the brain. Principal component analysis revealed that sets of upregulated metabolic enzyme genes in the FC and downregulated genes for signal transduction in the HPC can distinguish clearly between depressed and control animals, as well as explain the responsiveness to antidepressants. This comprehensive data could help to unravel the complex genetic predispositions involved in human depression. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
150. Enhancing the Technology of Clinical Trials and the Trials Model to Evaluate Newly Developed, Targeted Antidepressants
- Author
-
Katz, Martin M., Halbreich, Uriel M., Bowden, Charles L., Frazer, Alan, Pinder, Roger M., Rush, A. John, Wheatley, David P., and Lebowitz, Barry D.
- Subjects
ANTIDEPRESSANTS ,CLINICAL trials - Abstract
Concern about disappointing results from recent multi-center trials of new antidepressants prompted several ACNP workshops on “improving the technology of clinical trials.” The workshops focused on technical problems, such as patient screening, reliability of clinical ratings, and the role of the placebo control. They aimed to determine how to more effectively apply the current clinical trials model for evaluating antidepressant drugs. The problems confronting the field of clinical trials, however, extend beyond technology. They also included conceptual issues concerning changes in the understanding of depressive disorders and of the multiple actions of antidepressant drugs. Such problems have been further complicated by the rapidly changing field of drug development itself, which is continually refining the targeting of new antidepressant agents. Drugs are increasingly being developed to try to change specific behavioral facets more rapidly and may be less likely, therefore, to act initially on “whole” disorders. To address such issues, a symposium was held in Rhodes in 2000 that focused on such conceptual changes with the goal of developing recommendations to revise the clinical evaluation model. Its purpose was to integrate new knowledge on depression and the mechanisms of action of antidepressant drugs toward developing more efficient methods of drug development. Since the evaluation process will eventually require changes in governmental policy, senior staff from the National Institute of Mental Health (NIMH) and Food and Drug Administration (FDA) participated as well as members of academia, industry and clinical practice. Recommendations for altering clinical trial methodology were made in four areas: patient selection, methodology of evaluation, measuring onset of action, and FDA and NIMH perspectives on current practice. This article discusses these four areas and presents the consensus of the panel participants. [Copyright &y& Elsevier]
- Published
- 2002
- Full Text
- View/download PDF
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.