Antidepressant-like effects of neurokinin receptor antagonists in the forced swim test in the rat.

Dableh LJ, Yashpal K, Rochford J, Henry JL.

Department of Psychiatry, McGill University, Montreal, Quebec, Canada H3A 1A1.

Although a wide assortment of agents is currently available for the treatment of depression, this disorder remains poorly managed in a large proportion of patients. Traditional antidepressant treatments target the biogenic amine systems. However, a growing body of evidence is implicating the involvement of neuropeptides in depression, especially the neurokinin substance P. This study evaluated the effects of selective antagonists of the tachykinin NK1, NK2, and NK3 receptors in the forced swim test, a commonly used screen for antidepressants. Rats were given CP-96,345 (2S, 3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine, SR 48968 (S)-N-methyl-N[4-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-butyl]benzamide, or SR 142801 (S)-(N)-(1-(3-(1-benzoyl-3-(3,4-dichlorophenyl) piperidin-3-yl) propyl)-4-phenylpiperidin-4-yl)-N-methylacetamide, antagonists of the NK1, NK2, and NK3 receptors, respectively, at doses of 2.5, 5, and 10 mg/kg, intraperitoneally (i.p.). The time of immobility during the forced swim test was used as an indicator of antidepressant activity of the antagonists. All antagonists decreased immobility times. CP-96,345 and SR 142801 showed dose-related effects; SR 48968 had its maximum effect at 2.5 mg/kg. The magnitude of the effects of the neurokinin receptor antagonists was approximately the same as that of amitriptyline and desipramine, two traditional antidepressants, both given at 10 mg/kg, i.p. This study provides comparative data on the relative effectiveness of NK1, NK2, and NK3 receptor antagonists in this screen for antidepressant drug activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15659299&dopt=Abstract antidepressant




Antidepressant drug prescribing among elderly subjects: a population-based study.

Percudani M, Barbui C, Fortino I, Petrovich L.

Health Care Directorate, Region of Lombardy, Milan, Italy. Mauro_Percudani regione.lombardia.it

BACKGROUND: The patterns of antidepressant drug prescribing have rarely been studied in large and geographically defined populations of elderly subjects. In the present study we examined the prevalence and distribution of antidepressant prescribing in Lombardy, a northern Italy region with more than one and a half million elderly inhabitants. METHODS: We used the Regional Administrative Database of Lombardy. This database includes all prescriptions reimbursed by the National Health System in the population living in this region. All antidepressant prescriptions dispensed to subjects aged 65 years or above during 2001 were extracted and prevalence data calculated by dividing antidepressant users by the total number of male and female residents in each age group. RESULTS: During the 12 months surveyed 153,706 subjects were dispensed one or more prescriptions of antidepressants, yielding a prevalence of use of 9.49 subjects per 100 inhabitants (95% confidence interval 9.44, 9.53). Although the proportion of chronic users slightly decreased with age, more than 35% of those older that 85 years were moderate or chronic antidepressant users. General practitioners issued the majority of antidepressant prescriptions, and most antidepressant users were also dispensed agents for medical disorders. CONCLUSIONS: The very high rates of antidepressant drug prescribing detected in late life suggest the need of characterising these subjects in terms of medical and psychiatric characteristics, needs and quality of life. It also suggests the need for pragmatic clinical trials, carried out in the general practice, with the aim of assessing whether antidepressants are effective in these conditions. 2005 John Wiley & Sons, Ltd.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15660407&dopt=Abstract antidepressant




COMORBID CONDITIONS.

[No authors listed]

Staud R, Price DD, Robinson ME, Mauderli AP, Vierck CJ. Maintenance of windup of second pain requires less frequent stimulation in fibromyalgia patients compared to normal controls. Pain. 2004;110:689-696. Many chronic pain syndromes, including fibromyalgia (FM), show evidence of central nervous system hyperexcitability related to central sensitization. Windup (WU) of second pain reflects increased excitability of spinal cord neurons that is related to central sensitization. Psychophysical testing can help characterize this important central nervous system phenomenon because of the parallels between electrophysiological WU and WU of second pain. Animal experiments have shown that once WU has been established, only low frequency tonic nociceptive input is required to maintain the sensitized state of dorsal horn neurons (WU-maintenance or WU-M). The stimulus frequency necessary to maintain the hyperexcitability of spinal cord neurons can provide a measure of central sensitization. Because central sensitization plays an important role in many chronic pain syndromes including FM, we compared WU-M in 72 normal controls (NC) and 104 FM subjects. WU of second pain was produced by a train of 0.7-second duration thermal pulses applied to the glabrous surface of the hands at a frequency of 0.3 Hz. Enhanced second pain associated with WU could, thereafter, be maintained in FM but not NC subjects for up to 120 seconds by stimuli delivered at 0.16 and 0.08 Hz (WU-M stimuli). These two frequencies of stimulation do not produce WU when delivered alone. Thus, unlike NC subjects, FM subjects showed enhanced second pain during WU-M stimuli at very low stimulus frequencies, indicating central sensitization. Increased WU sensitivity, enhanced WU-M, and increased WU-related aftersensations help account for persistent pain conditions in FM subjects. In addition to WU, WU-M appears to be a useful tool to study mechanisms of pain in patients with characteristics of central sensitization. Comment: Interesting study as we become more and more concerned with central senitization in primary headache patients.-Stewart J. Tepper, MD Jick H, Kaye JA, Jick SS. Antidepressants and the risk of suicidal behaviors. JAMA. 2004;292:338-343. Background: The relation between the use of antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), and suicidal ideation and behaviors has received considerable public attention recently. The use of such drugs among teenagers has been of particular concern. Objective: To estimate the relative risks (RRs) of nonfatal suicidal behavior in patients starting treatment with one of three antidepressant drugs compared with patients starting treatment with dothiepin. Design and Setting: Matched case-control study of patients treated in UK general practices using the UK General Practice Research Database for 1993-1999.Participants: The base population included 159,810 users of the four antidepressant drugs. Participants could have used only one of these antidepressants and had to have received at least one prescription for the study antidepressant within 90 days before their index date (the date of suicidal behavior or ideation for cases and the same date for matched controls). Main Outcome Measures: Frequency of first-time exposure to amitriptyline, fluoxetine, paroxetine, and dothiepin of patients with a recorded diagnosis of first-time nonfatal suicidal behavior or suicide compared with comparable patients who did not exhibit suicidal behavior. Results: After controlling for age, sex, calendar time, and time from first antidepressant prescription to the onset of suicidal behavior, the relative risks for newly diagnosed nonfatal suicidal behavior in 555 cases and 2062 controls were 0.83 (95% confidence interval, [CI] 0.61-1.13) for amitriptyline, 1.16 (95% CI, 0.90-1.50) for fluoxetine, and 1.29 (95% CI, 0.97-1.70) for paroxetine compared with those using dothiepin. The RR for suicidal behavior among patients first prescribed an antidepressant within 1 to 9 days before their index date was 4.07 (95% CI, 2.89-5.74) compared with patients who were first prescribed an antidepressant 90 days or more before their index date. Time since first antidepressant prescription was not, however, a confounder of the relation between specific antidepressants and suicidal behavior since its relation to suicidal behavior was not materially different among users of the four study drugs. Similarly for fatal suicide, the RR among patients who were first prescribed an antidepressant within 1 to 9 days before their index date was 38 (95% CI, 6.2-231) compared with those who were first prescribed an antidepressant 90 days or more before their index date. There were no significant associations between the use of a particular study antidepressant and the risk of suicide. Conclusions: The risk of suicidal behavior after starting antidepressant treatment is similar among users of amitriptyline, fluoxetine, and paroxetine compared with the risk among users of dothiepin. The risk of suicidal behavior is increased in the first month after starting antidepressants, especially during the first 1 to 9 days. A possible small increase in risk (bordering statistical significance) among those starting the newest antidepressant, paroxetine, is of a magnitude that could readily be due to uncontrolled confounding by severity of depression. Based on limited information, we also conclude that there is no substantial difference in effect of the four drugs on people aged 10 to 19 years. Comment: This is an interesting study by the Boston collaborative group trying to unravel whether any of the antidepressants used in young people to treat a first attack of depressive illness were more likely to be linked to suicidal behavior. This was carried out using the UK General Practice Database which allows record linkage between diagnosis, treatment, and outcomes. As a primary care practitioner who contributes data to the GPRD, I am concerned that this study does not have the statistical power to exclude the possibility of an association. The authors rightly acknowledge the limited data upon which their conclusion is based. Moreover, the GPRD data base does not allow for the severity of depression to be categorized, hence the statement that "the possible small increase in risk (bordering statistical significance) among those starting the newest antidepressant, paroxetine, is of a magnitude that could readily be due to uncontrolled confounding by severity of depression" cannot be excluded using the GPRD.-David S. Millson, MD March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J, Treatment for Adolescents With Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA. 2004;292:807-820. Background: Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI). However, little is known about their relative or combined effectiveness. Objective: To evaluate the effectiveness of four treatments among adolescents with major depressive disorder. Design, Setting, and Participants: Randomized controlled trial of a volunteer sample of 439 patients between the ages of 12 and 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder. The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003. Interventions: Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and fluoxetine alone were administered double-blind; CBT alone and CBT with fluoxetine were administered unblinded. Main Outcome Measures: Children's Depression Rating Scale-Revised total score and, for responder analysis, a (dichotomized) Clinical Global Impressions improvement score. Results: Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P= 0.001) on the Children's Depression Rating Scale-Revised. Compared with fluoxetine alone (P= .02) and CBT alone (P= .01), treatment of fluoxetine with CBT was superior. Fluoxetine alone is a superior treatment to CBT alone (P= .01). Rates of response for fluoxetine with CBT were 71.0% (95% confidence interval [CI], 62%-80%); fluoxetine alone, 60.6% (95% CI, 51%-70%); CBT alone, 43.2% (95% CI, 34%-52%); and placebo, 34.8% (95% CI, 26%-44%). On the Clinical Global Impressions improvement responder analysis, the two fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all four treatment groups. Fluoxetine with CBT showed the greatest reduction (P= .02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides. Conclusion: The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder. Comment: The evidence is accumulating that the suicide risk may be up slightly due to the activating effects of the SSRIs when initially treating severe depression, especially in adolescents, though apparently less so with fluoxetine. The risk is reduced by having the patient simultaneously undergo Cognitive Behavioral Therapy (CBT). In headache management, we rarely have such severely depressed patients when we initiate therapy, but depression is co-morbid with migraine, and discussion of depression and mood is important before initiation of SSRI therapy.-Stewart J. Tepper, MD Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, Gould TD, Manji HK, Chen G. Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci. 2004;24:6590-6599. Manic-depressive illness has been conceptualized as a neurochemical illness. However, brain imaging and postmortem studies reveal gray-matter reductions, as well as neuronal and glial atrophy and loss in discrete brain regions of manic-depressive patients. The roles of such cerebral morphological deficits in the neuropathophysiology and therapeutic mechanisms of manic-depressive illness are unknown. Valproate (2-propylpentanoate) is a commonly used mood stabilizer. The ERK (extracellular signal-regulated kinase) pathway is used by neurotrophic factors to regulate neurogenesis, neurite outgrowth, and neuronal survival. We found that chronic treatment of rats with valproate increased levels of activated phospho-ERK44/42 in neurons of the anterior cingulate, a region in which we found valproate-induced increases in expression of an ERK pathway-regulated gene, bcl-2. Valproate time and concentration dependently increased activated phospho-ERK44/42 and phospho-RSK1 (ribosomal S6 kinase 1) levels in cultured cortical cells. These increases were attenuated by Raf and MEK (mitogen-activated protein kinase/ERK kinase) inhibitors. Although valproate affects the functions of GSK-3 (glycogen synthase kinase-3) and histone deacetylase (HDAC), its effects on the ERK pathway were not fully mimicked by selective inhibitors of GSK-3 or HDAC. Similar to neurotrophic factors, valproate enhanced ERK pathway-dependent cortical neuronal growth. Valproate also promoted neural stem cell proliferation-maturation (neurogenesis), demonstrated by bromodeoxyuridine (BrdU) incorporation and double staining of BrdU with nestin, Tuj1, or the neuronal nuclei marker NeuN (neuronal-specific nuclear protein). Chronic treatment with valproate enhanced neurogenesis in the dentate gyrus of the hippocampus. Together, these data demonstrate that valproate activates the ERK pathway and induces ERK pathway-mediated neurotrophic actions. This cascade of events provides a potential mechanism whereby mood stabilizers alleviate cerebral morphometric deficits associated with manic-depressive illness. Comment: Valproate has important structural effects on the brain in patients with bipolar illness, where underlying structural differences ("morphometic deficits") exist. Morphometic differences are also present in epilepsy patients, and it may not be a stretch to assume them in primary headache patients. So, the chronic effects of valproate are biochemical, electrical, and structural, and we are just beginning to understand them.-Stewart J. Tepper, MD.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15663629&dopt=Abstract antidepressant




Beta-1-adrenergic receptor gene in major depression: influence on antidepressant treatment response.

Zill P, Baghai TC, Engel R, Zwanzger P, Schule C, Minov C, Behrens S, Bottlender R, Jager M, Rupprecht R, Moller HJ, Ackenheil M, Bondy B.

Psychiatric Hospital of the Ludwig-Maximilians-University, Munich, Germany. Peter.Zill psy.med.uni-muenchen.de

Noradrenergic dysfunction has been implicated in the development of affective disorders. beta-adrenergic receptors (betaARs) mediate the response to norephinephrine, are coupled to the cAMP signaling cascade, supposed to be altered in their density and/or sensitivity in depression, and down regulated in several brain regions after long term treatment with different but not all antidepressants. A recently identified functional polymorphism in the beta(1)-adrenergic receptor (G1165C) leading to the amino acid variation Gly389Arg was associated with an enhanced coupling to the stimulatory G(s)-protein and increased adenylyl cyclase activation, disturbances which are often observed in affective disorders. Therefore, we investigated whether this beta(1)AR polymorphism is associated with major depression or with the response to antidepressant treatment in a sample of 259 patients compared to 206 healthy controls. Although we could not detect an association between the beta(1)AR polymorphism and major depression we found a tendency for a relation between CC homozygosity and a better and even faster response to antidepressant treatment in those patients, which were treated with antidepressants affecting directly or indirectly the beta(1)AR system (tricyclic antidepressants, noradrenergic and serotonergic specific agents, selective noradrenaline reuptake inhibitors) determined by the HAMD and CGI score (P = 0.05). However, after correction for multiple testing (Bonferroni) these results did not remain significant. Nevertheless, these findings suggest that the presence of the C allele might be an indicator for antidepressant treatment response. Copyright 2003 Wiley-Liss, Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12815745&dopt=Abstract antidepressant




Adherence to maintenance-phase antidepressant medication as a function of patient beliefs about medication.

Aikens JE, Nease DE Jr, Nau DP, Klinkman MS, Schwenk TL.

Department of Family Medicine, University of Michigan Medical School, Ann Arbor 48109, USA. aikensj umich.edu

PURPOSE: This study aimed to identify the demographic, psychiatric, and attitudinal predictors of treatment adherence during the maintenance phase of antidepressant treatment, ie, after symptoms and regimen are stabilized. METHODS: We surveyed 81 primary care patients given maintenance antidepressant medications regarding general adherence, recent missed doses, depression and treatment features, medication beliefs (necessity, concerns, harmfulness, and overprescription), and other variables. Additional data were collected from medical and payer records. RESULTS: Median treatment duration was 75 weeks. Adherence and beliefs were broadly dispersed and unrelated to treatment duration and type, physical functioning, and demographics. Multivariate analysis adjusting for social desirability, depression severity, and treatment duration indicated that an antidepressant-specific "necessity-minus-concerns" composite was strongly associated with both adherence outcomes. Specifically, adherence was highest when necessity exceeded concerns and lowest when concerns exceeded necessity. We crossed these 2 dimensions to characterize 4 patient attitudes toward antidepressants: skepticism, indifference, ambivalence, and acceptance. CONCLUSIONS: Patients given maintenance antidepressants vary widely in adherence. This variation is primarily explained by the balance between their perceptions of need and harmfulness of antidepressant medication, in that adherence is lowest when perceived harm exceeds perceived need, and highest when perceived need exceeds perceived harm. We speculate on ways to tailor adherence strategies to patient beliefs. Subsequent research should determine whether patients' perceptions about medication predict depression outcomes, can be used to improve clinical management, and respond to behavioral intervention.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15671187&dopt=Abstract antidepressant




Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways.

Taylor C, Fricker AD, Devi LA, Gomes I.

Department of Pharmacology and Biological Chemistry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.

Antidepressants are commonly used in the treatment of anxiety and depression, medical conditions that affect approximately 17-20% of the population. The clinical effects of antidepressants take several weeks to manifest, suggesting that these drugs induce adaptive changes in brain structures affected by anxiety and depression. In order to develop shorter-acting and more effective drugs for the treatment of anxiety and depression, it is important to understand how antidepressants bring about their beneficial effects. Recent reports suggest that antidepressants can induce neurogenesis in the adult brain, although the mechanisms involved are not clearly understood. In this review, we describe the different neurotransmitter systems that are affected by anxiety and depression and how they are modulated by antidepressant treatment with a focus on signaling molecules and pathways that are activated during neurotransmitter receptor induced neurogenesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15683730&dopt=Abstract antidepressant




Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus.

Sairanen M, Lucas G, Ernfors P, Castren M, Castren E.

Neuroscience Center, University of Helsinki, 00014 Helsinki, Finland.

Antidepressants increase proliferation of neuronal progenitor cells and expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. We investigated the role of BDNF signaling in antidepressant-induced neurogenesis by using transgenic mice with either reduced BDNF levels (BDNF+/-) or impaired trkB activation (trkB.T1-overexpressing mice). In both transgenic strains, chronic (21 d) imipramine treatment increased the number of bromodeoxyuridine (BrdU)-positive cells to degree similar to that seen in wild-type mice 24 h after BrdU administration, although the basal proliferation rate was increased in both transgenic strains. Three weeks after BrdU administration and the last antidepressant injection, the amount of newborn (BrdU- or TUC-4-positive) cells was significantly reduced in both BDNF+/- and trkB.T1-overexpressing mice, which suggests that normal BDNF signaling is required for the long-term survival of newborn hippocampal neurons. Moreover, the antidepressant-induced increase in the surviving BrdU-positive neurons seen in wild-type mice 3 weeks after treatment was essentially lost in mice with reduced BDNF signaling. Furthermore, we observed that chronic treatment with imipramine or fluoxetine produced a temporally similar increase in both BrdU-positive and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end-labeled neurons in the dentate gyrus, indicating that these drugs simultaneously increase both neurogenesis and neuronal elimination. These data suggest that antidepressants increase turnover of hippocampal neurons rather than neurogenesis per se and that BDNF signaling is required for the long-term survival of newborn neurons in mouse hippocampus.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15689544&dopt=Abstract antidepressant




The effects of CRF antagonists, antalarmin, CP154,526, LWH234, and R121919, in the forced swim test and on swim-induced increases in adrenocorticotropin in rats.

Jutkiewicz EM, Wood SK, Houshyar H, Hsin LW, Rice KC, Woods JH.

Department of Pharmacology, University of Michigan Medical School, 1301 MSRB 3, Ann Arbor, MI, 48109-0632, USA, ejutkiew umich.edu.

RATIONALE: Exposure to extreme stress has been suggested to produce long-term, detrimental alterations in the hypothalamic-pituitary-adrenal (HPA) axis leading to the development of mental disorders such as depression. Therefore, compounds that block the effects of stress hormones were investigated as potential therapeutics for depression. OBJECTIVES: In the present study, we compared the potential antidepressant-like effects of four CRF antagonists, antalarmin, CP154,526, R121919, and LWH234 (at 3, 10, and 30 mg/kg i.p., 60 min prior to the forced swim test) and the corresponding effect on swim-induced HPA activation to better elucidate the relation between HPA activity and antidepressant activity. METHODS: The antidepressant-like effects of the CRF antagonists and known antidepressants were determined in the rat forced swim test, and blood samples were obtained before and after swimming for the evaluation of adrenocorticotropin-releasing hormone (ACTH) levels. RESULTS: Antalarmin, CP154,526, and R121919 did not produce antidepressant-like effects in the forced swim test although these compounds decreased swim-induced increases in ACTH to various extents. In contrast, LWH234 reduced immobility in the forced swim test, without altering the swim-stress-induced ACTH response. However, this compound antagonized restraint-induced ACTH release. CONCLUSIONS: These data suggest that reducing stress-induced increases in HPA activity alone may not be sufficient to produce antidepressant-like activity; however, reductions in HPA activity may contribute to antidepressant actions of some treatments. In addition, it is proposed that CRF antagonists may alter differentially the HPA axis depending on the type of stressor used or behavioral measure evaluated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15696320&dopt=Abstract antidepressant